Trispecific binding molecules against bcma and uses thereof

ABSTRACT

The present disclosure provides multispecific binding molecules that specifically bind to BCMA, a component of a human T-cell receptor complex and either CD2 or a tumor associated antigen, conjugates comprising the multispecific binding molecules, and pharmaceutical compositions comprising the multispecific binding molecules and the conjugates The disclosure further provides methods of using the multispecific binding molecules to treat disease and disorders associated with expression of BCMA. The disclosure yet further provides recombinant host cells engineered to express the multispecific binding molecules and methods of producing the multispecific binding molecules by culturing the host cells under conditions in which the multispecific binding molecules are expressed.

1. CROSS-REFERNCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. provisionalapplication Nos. 62/850,889, filed May 21, 2019, and 62/854,667, filedMay 30, 2019, the contents of both of which are incorporated herein intheir entireties by reference thereto.

2. SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 13, 2020, isnamed NOV-005WO_SL.txt and is 595,602 bytes in size.

3. FIELD OF INVENTION

The disclosure generally relates to multispecific binding molecules thatengage BCMA, CD3 or other component of a TCR complex on T-cells, andeither CD2 or a human tumor-associated antigen (“TAA”), and their usefor treating diseases and disorders associated with expression of BCMA.

4. BACKGROUND

BCMA is a tumor necrosis family receptor (TNFR) member expressed oncells of the B-cell lineage. BCMA expression is the highest onterminally differentiated B cells that assume the long lived plasma cellfate, including plasma cells, plasmablasts and a subpopulation ofactivated B cells and memory B cells. BCMA is involved in mediating thesurvival of plasma cells for maintaining long-term humoral immunity. Theexpression of BCMA has been linked to a number of cancers, autoimmunedisorders, and infectious diseases. Cancers with increased expression ofBCMA include some hematological cancers, such as multiple myeloma,Hodgkin's and non-Hodgkin's lymphoma, various leukemias, andglioblastoma.

Redirected targeted T-cell lysis (RTCC) is an exciting mechanism forfirst line treatment and refractory settings. Antibodies and antibodyfragments with their exquisite selectivity have been successfullyengineered in a variety of formats to allow for the dual specificitiesrequired to cross-link T-cells to a single receptor on the target cell.

There is a need for improved RTCC approaches that target BCMA.

5. SUMMARY

The present disclosure extends the principles of redirected targetedT-cell lysis (RTCC) by providing multispecific binding molecules(“MBMs”) that engage BCMA, CD3 or other component of a T cell receptor(TCR) complex on T-cells, and either CD2 or a human tumor-associatedantigen (“TAA”). Without being bound by theory, the inventors believethat combining CD2- and TCR complex-engagement in a single multispecificmolecule can stimulate both a primary signaling pathway that promotesT-cell mediated lysis of tumor cells (by clustering TCRs, for example)and a second co-stimulatory pathway to induce T-cell proliferation andpotentially overcome anergy. Also without being bound by theory, it isbelieved that engaging a TAA in addition to BCMA and a component of aTCR complex will improve the clinical outcomes of RTCC therapy ofcancer, e.g., B cell malignancies by targeting a greater number ofcancerous B cells than using bispecific engagers that target only a BCMAand a TCR complex component.

In one aspect, the present disclosure provides MBMs (e.g., trispecificbinding molecules (“TBMs”)) that bind to (1) human BCMA, (2) CD3 orother component of a TCR complex, and (3) CD2.

In another aspect, the present disclosure provides MBMs (e.g.,trispecific binding molecules (“TBMs”)) that bind to (1) human BCMA, (2)CD3 or other component of a TCR complex, and (3) a TAA.

The MBMs (e.g., TBMs) comprise at least three antigen-binding modules(“ABMs”) that can bind (i) BCMA (ABM1), (ii) a component of a TCRcomplex (ABM2), and (iii) either CD2 or a TAA (ABM3). In someembodiments, each antigen-binding module is capable of binding itsrespective target at the same time as each of the other antigen-bindingmodules is bound to its respective target. ABM1 is immunoglobulin based,while ABM2 and ABM3 can be immunoglobulin- or non-immunoglobulin-based.Therefore the MBMs (e.g., TBMs) can include immunoglobulin-based ABMs orany combination of immunoglobulin- and non-immunoglobulin-based ABMs.Immunoglobulin-based ABMs that can be used in the MBMs (e.g., TBMs) aredescribed in Section 7.2.1 and specific embodiments 1 to 142, 145 to741, 782 to 793, 798 to 803, and 833 to 856, infra.Non-immunoglobulin-based ABMs that can be used in the MBMs (e.g., TBMs)are described in Section 7.2.2 and specific embodiments 143 to 144, 743to 782, and 795 to 797, infra. Further features of exemplary ABMs thatbind to human BCMA are described in Section 7.5 and specific embodiments1 to 142, infra. Further features of exemplary ABMs that bind to acomponent of a TCR complex are described in Section 7.6 and specificembodiments 151 to 741, infra. Further features of exemplary ABMs thatbind to CD2 are described in Section 7.7 and specific embodiments 742 to793, infra. Further features of exemplary ABMs that bind to TAAs aredescribed in Section 7.8 and specific embodiments 794 to 856, infra.

The ABMs of a MBM (e.g., TBM) (or portions thereof) can be connected toeach other, for example, by short peptide linkers or by an Fc domain.Methods and components for connecting ABMs to form a MBM are describedin Section 7.3 and specific embodiments 857 to 1159, infra.

MBMs (e.g., TBMs) have at least three ABMs (e.g., a TBM is at leasttrivalent), but can also have more than three ABMs. For example, a MBM(e.g., a TBM) can have four ABMs (i.e., is tetravalent), five ABMs(i.e., is pentavalent), or six ABMs (i.e., is hexavalent), provided thatthe MBM has at least one ABM that can bind BCMA, at least one ABM thatcan bind a component of a TCR complex, and at least one ABM that canbind either CD2 or a TAA. Exemplary trivalent, tetravalent, pentavalent,and hexavalent TBM configurations are shown in FIG. 1 and described inSection 7.4 and specific embodiments 1160 to 1263, infra.

The disclosure further provides nucleic acids encoding the MBMs (eitherin a single nucleic acid or a plurality of nucleic acids) andrecombinant host cells and cell lines engineered to express the nucleicacids and MBMs of the disclosure. Exemplary nucleic acids, host cells,and cell lines are described in Section 7.9 and specific embodiments1653 to 1660, infra.

The present disclosure further provides drug conjugates comprising theMBMs of the disclosure. Such conjugates are referred to herein as“antibody-drug conjugates” or “ADCs” for convenience, notwithstandingthat some of the ABMs can be non-immunoglobulin domains. Examples ofADCs are described in Section 7.10 and specific embodiments 1396 to1435, infra.

Pharmaceutical compositions comprising the MBMs and ADCs are alsoprovided. Examples of pharmaceutical compositions are described inSection 7.11 and specific embodiment 1494, infra.

Further provided herein are methods of using the MBMs, the ADCs, and thepharmaceutical compositions of the disclosure, for example for treatingproliferative conditions (e.g., cancers), on which BCMA is expressed,for treating autoimmune disorders, and for treating other diseases andconditions associated with expression of BCMA. Exemplary methods aredescribed in Section 7.12 and specific embodiments 1495 to 1575, infra.

The disclosure further provides methods of using the MBMs, the ADCs, andthe pharmaceutical compositions in combination with other agents andtherapies. Exemplary agents, therapies, and methods of combinationtherapy are described in Section 7.13 and specific embodiments 1576 to1652, infra.

6. BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1V: Exemplary TBM configurations. FIG. 1A illustratescomponents of the exemplary TBM configurations illustrated in FIGS.1B-1V. Not all regions connecting the different domains of each chainare illustrated (e.g., the linker connecting the VH and VL domains of anscFv, the hinge connecting the CH2 and CH3 domains of an Fc, etc., areomitted). FIG. 1B-1P illustrates trivalent TBMs; FIGS. 1Q-1S illustratetetravalent TBMs; FIG. 1T illustrates a pentavalent TBM, and FIGS. 1U-1Villustrate hexavalent TBMs.

FIGS. 2A-2B: Schematics of the trispecific constructs of Example 2.

FIGS. 3A-3F: Results of RTCC assay of Example 2. FIG. 3A: E:T ratio of5:1; FIG. 3B: E:T ratio of 3:1; FIG. 30 : ET ratio of 1:1; FIG. 3D: E:Tratio of 1:3; FIG. 3E: E:T ratio of 1:5; FIG. 3F: figure legend.

FIGS. 4A-C: Measurements for cytokines IFN-y (FIG. 4A), IL-2 (FIG. 4B),and TNF-α (FIG. 4C) from cytokine release assay of Example 2 at E:Tratio of 1:5. From left to right in each figure, data is shown forAB3_TCR-CD58 trispecific, AB3_CD58 TCR trispecific, BSP, OAA,AB3_TCR-HEL bispecific.

FIG. 5 : A schematic representation of CD58.

7. DETAILED DESCRIPTION 7.1. Definitions

As used herein, the following terms are intended to have the followingmeanings:

ABM chain: Individual ABMs can ex ist as one (e.g., in the case of anscFv) polypeptide chain or form through the association of more than onepolypeptide chains (e.g., in the case of a Fab). As used herein, theterm “ABM chain” refers to all or a portion of an ABM that ex ists on asingle polypeptide chain. The use of the term “ABM chain” is intendedfor convenience and descriptive purposes only and does not connote aparticular configuration or method of production.

ADCC: By “ADCC” or “antibody dependent cell-mediated cytotoxicity” asused herein is meant the cell-mediated reaction where nonspecificcytotoxic cells that express FcγRs recognize bound antibody on a targetcell and subsequently cause lysis of the target cell. ADCC is correlatedwith binding to FcγRIIIa; increased binding to FcγRIIIa leads to anincrease in ADCC activity.

ADCP: By “ADCP” or antibody dependent cell-mediated phagocytosis as usedherein is meant the cell-mediated reaction where nonspecific phagocyticcells that express FcγRs recognize bound antibody on a target cell andsubsequently cause phagocytosis of the target cell.

Additional Agent: For convenience, an agent that is used in combinationwith a MBM is referred to herein as an “additional” agent.

Antibody: The term “antibody” as used herein refers to a polypeptide (orset of polypeptides) of the immunoglobulin family that is capable ofbinding an antigen non-covalently, reversibly and specifically. Forexample, a naturally occurring “antibody” of the IgG type is a tetramercomprising at least two heavy (H) chains and two light (L) chainsinter-connected by disulfide bonds. Each heavy chain is comprised of aheavy chain variable region (abbreviated herein as VH) and a heavy chainconstant region. The heavy chain constant region is comprised of threedomains, CH1, CH₂ and CH3. Each light chain is comprised of a lightchain variable region (abbreviated herein as VL) and a light chainconstant region. The light chain constant region is comprised of onedomain (abbreviated herein as CL). The VH and VL regions can be furthersubdivided into regions of hypervariability, termed complementaritydetermining regions (CDR), interspersed with regions that are moreconserved, termed framework regions (FR). Each VH and VL is composed ofthree CDRs and four FRs arranged from amino-terminus to carboxy-terminusin the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Thevariable regions of the heavy and light chains contain a binding domainthat interacts with an antigen. The constant regions of the antibodiescan mediate the binding of the immunoglobulin to host tissues orfactors, including various cells of the immune system (e.g., effectorcells) and the first component (Clq) of the classical complement system.The term “antibody” includes, but is not limited to, monoclonalantibodies, human antibodies, humanized antibodies, camelisedantibodies, chimeric antibodies, bispecific or multispecific antibodiesand anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Idantibodies to antibodies of the disclosure). The antibodies can be ofany isotype/class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) or subclass(e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).

Both the light and heavy chains are divided into regions of structuraland functional homology. The terms “constant” and “variable” are usedfunctionally. In this regard, it will be appreciated that the variabledomains of both the light (VL) and heavy (VH) chain portions determineantigen recognition and specificity. Conversely, the constant domains ofthe light chain (CL) and the heavy chain (CH1, CH2 or CH₃) conferimportant biological properties such as secretion, transplacentalmobility, Fc receptor binding, complement binding, and the like. Byconvention the numbering of the constant region domains increases asthey become more distal from the antigen-binding site or amino-terminusof the antibody. The N-terminus is a variable region and at theC-terminus is a constant region; the CH3 and CL domains actuallycomprise the carboxy-terminus of the heavy and light chain,respectively.

Antibody fragment: The term “antibody fragment” of an antibody as usedherein refers to one or more portions of an antibody. In someembodiments, these portions are part of the contact domain(s) of anantibody. In some other embodiments, these portion(s) areantigen-binding fragments that retain the ability of binding an antigennon-covalently, reversibly and specifically, sometimes referred toherein as the “antigen-binding fragment”, “antigen-binding fragmentthereof,” “antigen-binding portion”, and the like. Examples of bindingfragments include, but are not limited to, single-chain Fvs (scFv), aFab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1domains; a F(ab)2 fragment, a bivalent fragment comprising two Fabfragments linked by a disulfide bridge at the hinge region; a Fdfragment consisting of the VH and CH1 domains; a Fv fragment consistingof the VL and VH domains of a single arm of an antibody; a dAb fragment(Ward et al., (1989) Nature 341:544-546), which consists of a VH domain;and an isolated complementarity determining region (CDR). Thus, the term“antibody fragment” encompasses both proteolytic fragments of antibodies(e.g., Fab and F(ab)2 fragments) and engineered proteins comprising oneor more portions of an antibody (e.g., an scFv).

Antibody fragments can also be incorporated into single domainantibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies,tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, 2005,Nature Biotechnology 23: 1126-1136). Antibody fragments can be graftedinto scaffolds based on polypeptides such as Fibronectin type III (Fn3)(see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptidemonobodies).

Antibody fragments can be incorporated into single chain moleculescomprising a pair of tandem Fv segments (for example, VH-CH1-VH-CH1)which, together with complementary light chain polypeptides (forexample, VL-VC-VL-VC), form a pair of antigen-binding regions (Zapata etal., 1995, Protein Eng. 8:1057-1062; and U.S. Pat. No. 5,641,870).

Antibody Numbering System: In the present specification, the referencesto numbered amino acid residues in antibody domains are based on the EUnumbering system unless otherwise specified (for example, in Tables11C-1-11C-2). This system was originally devised by Edelman et al.,1969, Proc. Nat'l Acad. Sci. USA 63:78-85 and is described in detail inKabat et al., 1991, in Sequences of Proteins of Immunological Interest,US Department of Health and Human Services, NIH, USA.

Antigen-binding module: The term “antigen-binding module” or “ABM” asused herein refers to a portion of a MBM that has the ability to bind toan antigen non-covalently, reversibly and specifically. An ABM can beimmunoglobulin- or non-immunoglobulin-based. As used herein, the terms“ABM1” and “BCMA ABM” (and the like) refer to an ABM that bindsspecifically to BCMA, the terms “ABM2” and “TCR ABM” (and the like)refer to an ABM that binds specifically to a component of a TCR complex,the term “ABM3” refers to an ABM that binds specifically to CD2 or to aTAA (depending on context), the term “CD2 ABM” (and the like) refers toan ABM that binds specifically to CD2, and the term “TAA ABM” (and thelike) refers to an ABM that binds specifically to a TAA. The terms ABM1,ABM2, and ABM3 are used merely for convenience and are not intended toconvey any particular configuration of a MBM. In some embodiments, anABM2 binds to CD3 (referred to herein a “CD3 ABM” or the like).Accordingly, disclosures relating to ABM2 and ABM2s are also applicableto CD3 ABMs.

Antigen-binding domain: The term “antigen-binding domain” (ABD) refersto a portion of a molecule that has the ability to bind to an antigennon-covalently, reversibly and specifically. Exemplary antigen-bindingdomains include antigen-binding fragments and portions of bothimmunoglobulin and non-immunoglobulin based scaffolds that retain theability of binding an antigen non-covalently, reversibly andspecifically. As used herein, the term “antigen-binding domain”encompasses antibody fragments that retain the ability of binding anantigen non-covalently, reversibly and specifically.

Antigen-binding fragment: The term “antigen-binding fragment” of anantibody refers to a portion of an antibody that retains has the abilityto bind to an antigen non-covalently, reversibly and specifically.

Associated: The term “associated” in the context of a MBM refers to afunctional relationship between two or more polypeptide chains. Inparticular, the term “associated” means that two or more polypeptidesare associated with one another, e.g., non-covalently through molecularinteractions or covalently through one or more disulfide bridges orchemical cross-linkages, so as to produce a functional MBM (e.g., a TBM)in which ABM1, ABM2 and ABM3 can bind their respective targets. Examplesof associations that might be present in a MBM include (but are notlimited to) associations between Fc regions in an Fc domain (homodimericor heterodimeric as described in Section 7.3.1.5), associations betweenVH and VL regions in a Fab or Fv, and associations between CH1 and CL ina Fab.

B cell: As used herein, the term “B cell” refers to a cell of B celllineage, which is a type of white blood cell of the lymphocyte subtype.Examples of B cells include plasmablasts, plasma cells,lymphoplasmacytoid cells, memory B cells, follicular B cells, marginalzone B cells, B-1 cells, B-2 cells, and regulatory B cells.

B cell malignancy: As used herein, a B cell malignancy refers to anuncontrolled proliferation of B cells. Examples of B cell malignancyinclude non-Hodgkin's lymphomas (NHL), Hodgkin's lymphomas, leukemia,and myeloma. For example, a B cell malignancy can be, but is not limitedto, multiple myeloma, chronic lymphocytic leukemia (CLL)/smalllymphocytic lymphoma (SLL), follicular lymphoma, mantle cell lymphoma(MCL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphomas,Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrommacroglobulinemia), hairy cell leukemia, primary central nervous system(CNS) lymphoma, primary mediastinal large B-cell lymphoma, mediastinalgrey-zone lymphoma (MGZL), splenic marginal zone B-cell lymphoma,extranodal marginal zone B-cell lymphoma of MALT, nodal marginal zoneB-cell lymphoma, and primary effusion lymphoma, and plasmacyticdendritic cell neoplasms.

BCMA: As used herein, the term “BCMA” refers to B-cell maturationantigen. BCMA (also known as TNFRSF17, BCM or CD269) is a member of thetumor necrosis receptor (TNFR) family and is predominantly expressed onterminally differentiated B cells, e.g., memory B cells and plasmacells. Its ligands include B-cell activating factor (BAFF) and aproliferation-inducing ligand (APRIL). The protein BCMA is encoded bythe gene TNFRSF17. Exemplary BCMA sequences are available at the Uniprotdatabase under accession number Q02223.

Binding Sequences: In reference to Tables 11, 12, 13, 14, or 17(including subparts thereof), the term “binding sequences” means an ABMhaving a full set of CDRs, a VH-VL pair, or an scFv set forth in thattable.

Bivalent: The term “bivalent” as used herein in the context of anantigen-binding molecule refers to an antigen-binding molecule that hastwo antigen-binding domains. The domains can be the same or different.Accordingly, a bivalent antigen-binding molecule can be monospecific orbispecific.

Cancer: The term “cancer” refers to a disease characterized by theuncontrolled (and often rapid) growth of aberrant cells. Cancer cellscan spread locally or through the bloodstream and lymphatic system toother parts of the body. Examples of various cancers are describedherein and include but are not limited to, leukemia, multiple myeloma,asymptomatic myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma,e.g., any BCMA-positive cancers of any of the foregoing types. The term“cancerous B cell” refers to a B cell that is undergoing or hasundergone uncontrolled proliferation

CD3: The term “CD3” or “cluster of differentiation 3” refers to thecluster of differentiation 3 co-receptor of the T cell receptor. CD3helps in activation of both cytotoxic T-cell (e.g., CD830 naïve T cells)and T helper cells (e.g., CD4+naïve T cells) and is composed of fourdistinct chains: one CD3γ chain (e.g., Genbank Accession NumbersNM_000073 and MP_000064 (human)), one CD3δ chain (e.g., GenbankAccession Numbers NM_000732, NM_001040651, NP_00732 and NP_001035741(human)), and two CD3ϵ chains (e.g., Genbank Accession Numbers NM_000733 and NP_00724 (human)). The chains of CD3 are highly relatedcell-surface proteins of the immunoglobulin superfamily containing asingle extracellular immunoglobulin domain. The CD3 molecule associateswith the T-cell receptor (TCR) and chain to form the T-cell receptor(TCR) complex, which functions in generating activation signals in Tlymphocytes.

Unless expressly indicated otherwise, the reference to CD3 in theapplication can refer to the CD3 co-receptor, the CD3 co-receptorcomplex, or any polypeptide chain of the CD3 co-receptor complex.

Chimeric Antibody: The term “chimeric antibody” (or antigen-bindingfragment thereof) is an antibody molecule (or antigen-binding fragmentthereof) in which (a) the constant region, or a portion thereof, isaltered, replaced or exchanged so that the antigen-binding site(variable region) is linked to a constant region of a different oraltered class, effector function and/or species, or an entirelydifferent molecule which confers new properties to the chimericantibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or(b) the variable region, or a portion thereof, is altered, replaced orexchanged with a variable region having a different or altered antigenspecificity. For example, a mouse antibody can be modified by replacingits constant region with the constant region from a humanimmunoglobulin. Due to the replacement with a human constant region, thechimeric antibody can retain its specificity in recognizing the antigenwhile having reduced antigenicity in human as compared to the originalmouse antibody.

In combination: Administered “in combination,” as used herein, meansthat two (or more) different treatments are delivered to the subjectduring the course of the subject's affliction with the disorder, e.g.,the two or more treatments are delivered after the subject has beendiagnosed with the disorder and before the disorder has been cured oreliminated or treatment has ceased for other reasons.

Complementarity Determininci Rection: The terms “complementaritydetermining region” or “CDR,” as used herein, refer to the sequences ofamino acids within antibody variable regions which confer antigenspecificity and binding affinity. For example, in general, there arethree CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2,and CDR-H3) and three CDRs in each light chain variable region (CDR-L1,CDR-L2, and CDR-L3). The precise amino acid sequence boundaries of agiven CDR can be determined using any of a number of well-known schemes,including those described by Kabat et al., 1991, “Sequences of Proteinsof Immunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, MD (“Kabat” numbering scheme),Al-Lazikani et al., 1997, JMB 273:927-948 (“Chothia” numbering scheme)and ImMunoGenTics (IMGT) numbering (Lefranc, 1999, The Immunologist7:132-136 (1999); Lefranc et al., 2003, Dev. Comp. Immunol. 27:55-77(“IMGT” numbering scheme). For example, for classic formats, underKabat, the CDR amino acid residues in the heavy chain variable domain(VH) are numbered 31-35 (CDR-H1), 50-65 (CDR-H2), and 95-102 (CDR-H₃);and the CDR amino acid residues in the light chain variable domain (VL)are numbered 24-34 (CDR-L1), 50-56 (CDR-L2), and 89-97 (CDR-L3). UnderChothia, the CDR amino acids in the VH are numbered 26-32 (CDR-H1),52-56 (CDR-H2), and 95-102 (CDR-H₃); and the amino acid residues in VLare numbered 26-32 (CDR-L1), 50-52 (CDR-L2), and 91-96 (CDR-L3). Bycombining the CDR definitions of both Kabat and Chothia, the CDRsconsist of amino acid residues 26-35 (CDR-H1), 50-65 (CDR-H2), and95-102 (CDR-H₃) in human VH and amino acid residues 24-34 (CDR-L1),50-56 (CDR-L2), and 89-97 (CDR-L3) in human VL. Under IMGT the CDR aminoacid residues in the VH are numbered approximately 26-35 (CDR-H1), 51-57(CDR-H2) and 93-102 (CDR-H₃), and the CDR amino acid residues in the VLare numbered approximately 27-32 (CDR-L1), 50-52 (CDR-L2), and 89-97(CDR-L3) (numbering according to “Kabat”). Under IMGT, the CDR regionsof an antibody can be determined using the program IMGT/DomainGap Align.

Concurrently: The term “concurrently” is not limited to theadministration of therapies (e.g., prophylactic or therapeutic agents)at exactly the same time, but rather it is meant that a pharmaceuticalcomposition comprising MBM or ADC is administered to a subject in asequence and within a time interval such that the molecules can acttogether with the additional therapy(ies) to provide an increasedbenefit than if they were administered otherwise.

Conservative Sequence Modifications: The term “conservative sequencemodifications” refers to amino acid modifications that do notsignificantly affect or alter the binding characteristics of a MBM or acomponent thereof (e.g., an ABM or an Fc region). Such conservativemodifications include amino acid substitutions, additions and deletions.Modifications can be introduced into a MBM by standard techniques, suchas site-directed mutagenesis and PCR-mediated mutagenesis. Conservativeamino acid substitutions are ones in which the amino acid residue isreplaced with an amino acid residue having a similar side chain.Families of amino acid residues having similar side chains have beendefined in the art. These families include amino acids with basic sidechains (e.g., lysine, arginine, histidine), acidic side chains (e.g.,aspartic acid, glutamic acid), uncharged polar side chains (e.g.,glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine,tryptophan), nonpolar side chains (e.g., alanine, valine, leucine,isoleucine, proline, phenylalanine, methionine), beta-branched sidechains (e.g., threonine, valine, isoleucine) and aromatic side chains(e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one ormore amino acid residues within a MBM can be replaced with other aminoacid residues from the same side chain family and the altered MBM can betested for, e.g., binding to target molecules and/or effectiveheterodimerization and/or effector function.

Diabody: The term “diabody” as used herein refers to small antibodyfragments with two antigen-binding sites, typically formed by pairing ofscFv chains. Each scFv comprises a heavy chain variable domain (VH)connected to a light chain variable domain (VL) in the same polypeptidechain (VH-VL, where the VH is either N-terminal or C-terminal to theVL). Unlike a typical scFv in which the VH and VL are separated by alinker that allows the VH and VL on the same polypeptide chain to pairand form an antigen-binding domain, diabodies typically comprise alinker that is too short to allow pairing between the VH and VL domainson the same chain, forcing the VH and VL domains to pair with thecomplementary domains of another chain and create two antigen-bindingsites. Diabodies are described more fully in, for example, EP 404,097;WO 93/11161; and Hollinger et al., 1993, Proc. Natl. Acad. Sci. USA90:6444-6448.

dsFv: The term “dsFv” refers to disulfide-stabilized Fv fragments. In adsFv, a VH and VL are connected by an interdomain disulfide bond. Togenerate such molecules, one amino acid each in the framework region ofin VH and VL are mutated to a cysteine, which in turn form a stableinterchain disulfide bond. Typically, position 44 in the VH and position100 in the VL are mutated to cysteines. See Brinkmann, 2010, AntibodyEngineering 181-189, D01:10.1007/978-3-642-01147-4_14. The term dsFvencompasses both what is known as a dsFv (a molecule in which the VH andVL are connected by an interchain disulfide bond but not a linkerpeptide) or scdsFv (a molecule in which the VH and VL are connected by alinker as well as an interchain disulfide bond).

Effector Function: The term “effector function” refers to an activity ofan antibody molecule that is mediated by binding through a domain of theantibody other than the antigen-binding domain, usually mediated bybinding of effector molecules. Effector function includescomplement-mediated effector function, which is mediated by, forexample, binding of the Cl component of the complement to the antibody.Activation of complement is important in the opsonization and lysis ofcell pathogens. The activation of complement also stimulates theinflammatory response and may also be involved in autoimmunehypersensitivity. Effector function also includes Fc receptor(FcR)-mediated effector function, which can be triggered upon binding ofthe constant domain of an antibody to an Fc receptor (FcR). Binding ofantibody to Fc receptors on cell surfaces triggers a number of importantand diverse biological responses including engulfment and destruction ofantibody-coated particles, clearance of immune complexes, lysis ofantibody-coated target cells by killer cells (called antibody-dependentcell-mediated cytotoxicity, or ADCC), release of inflammatory mediators,placental transfer and control of immunoglobulin production. An effectorfunction of an antibody can be altered by altering, e.g., enhancing orreducing, the affinity of the antibody for an effector molecule such asan Fc receptor or a complement component. Binding affinity willgenerally be varied by modifying the effector molecule binding site, andin this case it is appropriate to locate the site of interest and modifyat least part of the site in a suitable way. It is also envisaged thatan alteration in the binding site on the antibody for the effectormolecule need not alter significantly the overall binding affinity butmay alter the geometry of the interaction rendering the effectormechanism ineffective as in non-productive binding. It is furtherenvisaged that an effector function may also be altered by modifying asite not directly involved in effector molecule binding, but otherwiseinvolved in performance of the effector function.

Epitope: An epitope, or antigenic determinant, is a portion of anantigen recognized by an antibody or other antigen-binding moiety asdescribed herein. An epitope can be linear or conformational.

Fab: By “Fab” or “Fab region” as used herein is meant a polypeptideregion that comprises the VH, CH1, VL, and CL immunoglobulin domain.These terms can refer to this region in isolation, or this region in thecontext of an antigen-binding molecule of the disclosure.

Fab domains are formed by association of a CH1 domain attached to a VHdomain with a CL domain attached to a VL domain. The VH domain is pairedwith the VL domain to constitute the Fv region, and the CH1 domain ispaired with the CL domain to further stabilize the binding module. Adisulfide bond between the two constant domains can further stabilizethe Fab domain.

Fab regions can be produced by proteolytic cleavage of immunoglobulinmolecules (e.g., using enzymes such as papain) or through recombinantexpression. In native immunoglobulin molecules, Fabs are formed byassociation of two different polypeptide chains (e.g., VH-CH1 on onechain associates with VL-CL on the other chain). The Fab regions aretypically expressed recombinantly, typically on two polypeptide chains,although single chain Fabs are also contemplated herein.

Fc domain: The term “Fc domain” refers to a pair of associated Fcregions. The two Fc regions dimerize to create the Fc domain. The two Fcregions within the Fc domain can be the same (such an Fc domain beingreferred to herein as an “Fc homodimer”) or different from one another(such an Fc domain being referred to herein as an “Fc heterodimer”).

Fc region: The term “Fc region” or “Fc chain” as used herein is meantthe polypeptide comprising the CH₂—CH3 domains of an IgG molecule, andin some cases, inclusive of the hinge. In EU numbering for human IgG1,the CH₂—CH3 domain comprises amino acids 231 to 447, and the hinge is216 to 230. Thus the definition of “Fc region” includes both amino acids231-447 (CH₂—CH₃) or 216-447 (hinge-CH2—CH₃), or fragments thereof. An“Fc fragment” in this context can contain fewer amino acids from eitheror both of the N- and C-termini but still retains the ability to form adimer with another Fc region as can be detected using standard methods,generally based on size (e.g., non-denaturing chromatography, sizeexclusion chromatography). Human IgG Fc regions are of particular use inthe present disclosure, and can be the Fc region from human IgG1, IgG2or IgG4.

Fv: The term “Fv” refers to the minimum antibody fragment derivable froman immunoglobulin that contains a complete target recognition andbinding site. This region consists of a dimer of one heavy and one lightchain variable domain in a tight, noncovalent association (VH-VL dimer).It is in this configuration that the three CDRs of each variable domaininteract to define a target binding site on the surface of the VH-VLdimer. Often, the six CDRs confer target binding specificity to theantibody. However, in some instances even a single variable domain (orhalf of an Fv comprising only three CDRs specific for a target) can havethe ability to recognize and bind target. The reference to a VH-VL dimerherein is not intended to convey any particular configuration. By way ofexample and not limitation, the VH and VL can come together in anyconfiguration described herein to form a half antibody, or can each bepresent on a separate half antibody and come together to form an antigenbinding domain when the separate half antibodies associate, for exampleto form a TBM of the disclosure. When present on a single polypeptidechain (e.g., a scFv), the VH and be N-terminal or C-terminal to the VL.

Half Antibody: The term “half antibody” refers to a molecule thatcomprises at least one ABM or ABM chain and can associate with anothermolecule comprising an ABM or ABM chain through, e.g., a disulfidebridge or molecular interactions (e.g., knob-in-hole interactionsbetween Fc heterodimers). A half antibody can be composed of onepolypeptide chain or more than one polypeptide chains (e.g., the twopolypeptide chains of a Fab). In an embodiment, a half-antibodycomprises an Fc region.

An example of a half antibody is a molecule comprising a heavy and lightchain of an antibody (e.g., an IgG antibody). Another example of a halfantibody is a molecule comprising a first polypeptide comprising a VLdomain and a CL domain, and a second polypeptide comprising a VH domain,a CH1 domain, a hinge domain, a CH2 domain, and a CH3 domain, where theVL and VH domains form an ABM. Yet another example of a half antibody isa polypeptide comprising an scFv domain, a CH2 domain and a CH3 domain.

A half antibody might include more than one ABM, for example ahalf-antibody comprising (in N- to C-terminal order) an scFv domain, aCH2 domain, a CH3 domain, and another scFv domain.

Half antibodies might also include an ABM chain that when associatedwith another ABM chain in another half antibody forms a complete ABM.

Thus, a MBM (e.g., a TBM) can comprise one, more typically two, or evenmore than two half antibodies, and a half antibody can comprise one ormore ABMs or ABM chains.

In some MBMs, a first half antibody will associate, e.g.,heterodimerize, with a second half antibody. In other MBMs, a first halfantibody will be covalently linked to a second half antibody, forexample through disulfide bridges or chemical crosslinking. In yet otherMBMs, a first half antibody will associate with a second half antibodythrough both covalent attachments and non-covalent interactions, forexample disulfide bridges and knob-in-hole interactions.

The term “half antibody” is intended for descriptive purposes only anddoes not connote a particular configuration or method of production.Descriptions of a half antibody as a “first” half antibody, a “second”half antibody, a “left” half antibody, a “right” half antibody or thelike are merely for convenience and descriptive purposes.

Hexavalent: The term “hexavalent” as used herein in the context of anantigen-binding molecule (e.g., a TBM) refers to an antigen-bindingmolecule that has six antigen-binding domains. Hexavalent TBMs of thedisclosure generally have three pairs of antigen-binding domains thateach bind to the same antigen, although different configurations (e.g.,three antigen-binding domains that bind to BCMA, two antigen-bindingdomains that bind to a component of a TCR complex, and oneantigen-binding domain that binds to CD2 or a TAA, or threeantigen-binding domains that bind to BCMA, two antigen-binding domainsthat bind to CD2 or a TAA, and one antigen-binding domain that binds toa component of a TCR complex) are within the scope of the disclosure.Examples of hexavalent TBMs are shown schematically in FIGS. 1U-1V.

Hole: In the context of a knob-into-hole, a “hole” refers to at leastone amino acid side chain which is recessed from the interface of afirst Fc chain and is therefore positionable in a compensatory “knob” onthe adjacent interfacing surface of a second Fc chain so as to stabilizethe Fc heterodimer, and thereby favor Fc heterodimer formation over Fchomodimer formation, for example.

Host cell or recombinant host cell: The terms “host cell” or“recombinant host cell” refer to a cell that has beengenetically-engineered, e.g., through introduction of a heterologousnucleic acid. It should be understood that such terms are intended torefer not only to the particular subject cell but to the progeny of sucha cell. Because certain modifications can occur in succeedinggenerations due to either mutation or environmental influences, suchprogeny may not, in fact, be identical to the parent cell, but are stillincluded within the scope of the term “host cell” as used herein. A hostcell can carry the heterologous nucleic acid transiently, e.g., on anextrachromosomal heterologous expression vector, or stably, e.g.,through integration of the heterologous nucleic acid into the host cellgenome. For purposes of expressing a MBM of the disclosure, a host cellcan be a cell line of mammalian origin or mammalian-likecharacteristics, such as monkey kidney cells (COS, e.g., COS-1, COS-7),HEK293, baby hamster kidney (BHK, e.g., BHK21), Chinese hamster ovary(CHO), NSO, PerC6, BSC-1, human hepatocellular carcinoma cells (e.g.,Hep G2), SP2/0, HeLa, Madin-Darby bovine kidney (MDBK), myeloma andlymphoma cells, or derivatives and/or engineered variants thereof. Theengineered variants include, e.g., glycan profile modified and/orsite-specific integration site derivatives.

Human Antibody: The term “human antibody” as used herein includesantibodies having variable regions in which both the framework and CDRregions are derived from sequences of human origin. Furthermore, if theantibody contains a constant region, the constant region also is derivedfrom such human sequences, e.g., human germline sequences, or mutatedversions of human germline sequences or antibody containing consensusframework sequences derived from human framework sequences analysis, forexample, as described in Knappik et al., 2000, J Mol Biol 296, 57-86.The structures and locations of immunoglobulin variable domains, e.g.,CDRs, can be defined using well known numbering schemes, e.g., the Kabatnumbering scheme, the Chothia numbering scheme, or a combination ofKabat and Chothia (see, e.g., Lazikani et al., 1997, J. Mol. Bio.273:927 948; Kabat et al., 1991, Sequences of Proteins of ImmunologicalInterest, 5th edit., NIH Publication no. 91-3242 U.S. Department ofHealth and Human Services; Chothia et al., 1987, J. Mol. Biol.196:901-917; Chothia et al., 1989, Nature 342:877-883).

Human antibodies can include amino acid residues not encoded by humansequences (e.g., mutations introduced by random or site-specificmutagenesis in vitro or by somatic mutation in vivo, or a conservativesubstitution to promote stability or manufacturing). However, the term“human antibody”, as used herein, is not intended to include antibodiesin which CDR sequences derived from the germline of another mammalianspecies, such as a mouse, have been grafted onto human frameworksequences.

Humanized: The term “humanized” forms of non-human (e.g., murine)antibodies are chimeric antibodies that contain minimal sequence derivedfrom non-human immunoglobulin. For the most part, humanized antibodiesare human immunoglobulins (recipient antibody) in which residues from ahypervariable region of the recipient are replaced by residues from ahypervariable region of a non-human species (donor antibody) such asmouse, rat, rabbit or non-human primate having the desired specificity,affinity, and capacity. In some instances, framework region (FR)residues of the human immunoglobulin are replaced by correspondingnon-human residues. Furthermore, humanized antibodies can compriseresidues that are not found in the recipient antibody or in the donorantibody. These modifications are made to further refine antibodyperformance. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the hypervariable loops correspondto those of a non-human immunoglobulin and all or substantially all ofthe FRs are those of a human immunoglobulin lo sequence. The humanizedantibody optionally will also comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin. For further details, see Jones et al., 1986, Nature321:522-525; Riechmann et al., 1988, Nature 332:323-329; and Presta,1992, Curr. Op. Struct. Biol. 2:593-596. See also the following reviewarticles and references cited therein: Vaswani and Hamilton, 1998, Ann.Allergy, Asthma & Immunol. 1:105-115; Harris, 1995, Biochem. Soc.Transactions 23:1035-1038; Hurle and Gross, 1994, Curr. Op. Biotech.5:428-433.

Knob: In the context of a knob-into-hole, a “knob” refers to at leastone amino acid side chain which projects from the interface of a firstFc chain and is therefore positionable in a compensatory “hole” in theinterface with a second Fc chain so as to stabilize the Fc heterodimer,and thereby favor Fc heterodimer formation over Fc homodimer formation,for example.

Knobs and holes (or knobs-into-holes): One mechanism for Fcheterodimerization is generally referred to in the art as “knobs andholes”, or “knob-in-holes”, or “knobs-into-holes”. These terms refer toamino acid mutations that create steric influences to favor formation ofFc heterodimers over Fc homodimers, as described in, e.g., Ridgway etal., 1996, Protein Engineering 9(7):617; Atwell et al., 1997, J. Mol.Biol. 270:26; and U.S. Pat. No. 8,216,805. Knob-in-hole mutations can becombined with other strategies to improve heterodimerization, forexample as described in Section 7.3.1.6.

Monoclonal Antibody: The term “monoclonal antibody” as used hereinrefers to polypeptides, including antibodies, antibody fragments,molecules (including TBMs), etc. that are derived from the same geneticsource.

Monovalent: The term “monovalent” as used herein in the context of anantigen-binding molecule refers to an antigen-binding molecule that hasa single antigen-binding domain.

Multispecific bindinci molecules: The term “multispecific bindingmolecules” or “MBMs” refers to molecules that specifically bind to atleast two antigens and comprise two or more antigen-binding domains. Theantigen-binding domains can each independently be an antibody fragment(e.g., scFv, Fab, nanobody), a ligand, or a non-antibody derived binder(e.g., fibronectin, Fynomer, DARPin).

Mutation or modification: In the context of the primary amino acidsequence of a polypeptide, the terms “modification” and “mutation” referto an amino acid substitution, insertion, and/or deletion in thepolypeptide sequence relative to a reference polypeptide. Additionally,the term “modification” further encompasses an alteration to an aminoacid residue, for example by chemical conjugation (e.g., of a drug orpolyethylene glycol moiety) or post-translational modification (e.g.,glycosylation).

Nucleic Acid: The term “nucleic acid” is used herein interchangeablywith the term “polynucleotide” and refers to deoxyribonucleotides orribonucleotides and polymers thereof in either single- ordouble-stranded form. The term encompasses nucleic acids containingknown nucleotide analogs or modified backbone residues or linkages,which are synthetic, naturally occurring, and non-naturally occurring,which have similar binding properties as the reference nucleic acid, andwhich are metabolized in a manner similar to the reference nucleotides.Examples of such analogs include, without limitation, phosphorothioates,phosphoramidates, methyl phosphonates, chiral-methyl phosphonates,2-O-methyl ribonucleotides, and peptide-nucleic acids (PNAs).

Unless otherwise indicated, a particular nucleic acid sequence alsoimplicitly encompasses conservatively modified variants thereof (e.g.,degenerate codon substitutions) and complementary sequences, as well asthe sequence explicitly indicated. Specifically, as detailed below,degenerate codon substitutions can be achieved by generating sequencesin which the third position of one or more selected (or all) codons issubstituted with mixed-base and/or deoxyinosine residues (Batzer et al.,(1991) Nucleic Acid Res. 19:5081; Ohtsuka et al., (1985) J. Biol. Chem.260:2605-2608; and Rossolini et al., (1994) Mol. Cell. Probes 8:91-98).

Operably linked: The term “operably linked” refers to a functionalrelationship between two or more peptide or polypeptide domains ornucleic acid (e.g., DNA) segments. In the context of a fusion protein orother polypeptide, the term “operably linked” means that two or moreamino acid segments are linked so as to produce a functionalpolypeptide. For example, in the context of a MBM of the disclosure,separate ABMs (or chains of an ABM) can be through peptide linkersequences. In the context of a nucleic acid encoding a fusion protein,such as a polypeptide chain of a MBM of the disclosure, “operablylinked” means that the two nucleic acids are joined such that the aminoacid sequences encoded by the two nucleic acids remain in-frame. In thecontext of transcriptional regulation, the term refers to the functionalrelationship of a transcriptional regulatory sequence to a transcribedsequence. For example, a promoter or enhancer sequence is operablylinked to a coding sequence if it stimulates or modulates thetranscription of the coding sequence in an appropriate host cell orother expression system.

Pentavalent: The term “pentavalent” as used herein in the context of anantigen-binding molecule (e.g., a TBM) refers to an antigen-bindingmolecule that has five antigen-binding domains. Pentavalent TBMs of thedisclosure generally have either (a) two pairs of antigen-bindingdomains that each bind to the same antigen and a single antigen-bindingdomain that binds to the third antigen or (b) three antigen-bindingdomains that bind to the same antigen and two antigen-binding domainsthat each bind to a separate antigen. An example of a pentavalent TBM isshown schematically in FIG. 1T.

Polypeptide and Protein: The terms “polypeptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues. Theterms encompass amino acid polymers in which one or more amino acidresidue is an artificial chemical mimetic of a corresponding naturallyoccurring amino acid, as well as to naturally occurring amino acidpolymers and non-naturally occurring amino acid polymer. Additionally,the terms encompass amino acid polymers that are derivatized, forexample, by synthetic derivatization of one or more side chains ortermini, glycosylation, PEGylation, circular permutation, cyclization,linkers to other molecules, fusion to proteins or protein domains, andaddition of peptide tags or labels.

Recognize: The term “recognize” as used herein refers to an ABM thatfinds and interacts (e.g., binds) with its epitope.

Sequence identity: Sequence identity between two similar sequences(e.g., antibody variable domains) can be measured by algorithms such asthat of Smith, T. F. & Waterman, M. S. (1981) “Comparison OfBiosequences,” Adv. Appl. Math. 2:482 [local homology algorithm];Needleman, S. B. & Wunsch, C D. (1970) “A General Method Applicable ToThe Search For Similarities In The Amino Acid Sequence Of Two Proteins,”J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W. R. &Lipman, D. J. (1988) “Improved Tools For Biological SequenceComparison,” Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search forsimilarity method]; or Altschul, S.F. et al, (1990) “Basic LocalAlignment Search Tool,” J. Mol. Biol. 215:403-10 , the “BLAST”algorithm, see blast.ncbi.nlm.nih.gov/Blast.cgi. When using any of theaforementioned algorithms, the default parameters (for Window length,gap penalty, etc.) are used. In one embodiment, sequence identity isdone using the BLAST algorithm, using default parameters.

Optionally, the identity is determined over a region that is at leastabout 50 nucleotides (or, in the case of a peptide or polypeptide, atleast about 10 amino acids) in length, or in some cases over a regionthat is 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or moreamino acids) in length. In some embodiments, the identity is determinedover a defined domain, e.g., the VH or VL of an antibody. Unlessspecified otherwise, the sequence identity between two sequences isdetermined over the entire length of the shorter of the two sequences.

Sincile Chain Fab or scFab: The terms “single chain Fab” and “scFab”mean a polypeptide comprising an antibody heavy chain variable domain(VH), an antibody constant domain 1 (CH1), an antibody light chainvariable domain (VL), an antibody light chain constant domain (CL) and alinker, such that the VH and VL are in association with one another andthe CH1 and CL are in association with one another. In some embodiments,the antibody domains and the linker have one of the following orders inN-terminal to C-terminal direction: a) VH-CH1-linker-VL-CL, b)VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1 or d) VL-CH1-linker-VH-CL.The linker can be a polypeptide of at least 30 amino acids, for examplebetween 32 and 50 amino acids. The single chain Fabs are stabilized viathe natural disulfide bond between the CL domain and the CH1 domain.

Sincile Chain Fv or scFv: The term “single-chain Fv” or “scFv” as usedherein refers to antibody fragments comprise the VH and VL domains of anantibody, where these domains are present in a single polypeptide chain.The Fv polypeptide can further comprise a polypeptide linker between theVH and VL domains which enables the scFv to form the desired structurefor antigen-binding. For a review of scFv see Plückthun in ThePharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Mooreeds., (1994) Springer-Verlag, New York, pp. 269-315.

Specifically (or selectively) binds: The term “specifically (orselectively) binds” to an antigen or an epitope refers to a bindingreaction that is determinative of the presence of a cognate antigen oran epitope in a heterogeneous population of proteins and otherbiologics. The binding reaction can be but need not be mediated by anantibody or antibody fragment, but can also be mediated by, for example,any type of ABM described in Section 7.2, such as a ligand, a DARPin,etc. An ABM typically also has a dissociation rate constant (KD)(koff/kon) of less than 5×10⁻² M, less than 10⁻² M, less than 5×10⁻³ M,less than 10⁻³ M, less than 5×10⁻⁴ M, less than 10⁻⁴ M, less than 5×10⁻⁵M, less than 10⁻⁵ M, less than 5×10⁻⁶ M, less than 10⁻⁶ M, less than5×10⁻⁷ M, less than 10⁻⁷ M, less than 5×10⁻⁸ M, less than 10⁻⁸ M, lessthan 5×10⁻⁹ M, or less than 10⁻⁹ M, and binds to the target antigen withan affinity that is at least two-fold greater than its affinity forbinding to a non-specific antigen (e.g., HSA). The term “specificallybinds” does not exclude cross-species reactivity. For example, anantigen-binding module (e.g., an antigen-binding fragment of anantibody) that “specifically binds” to an antigen from one species canalso “specifically bind” to that antigen in one or more other species.Thus, such cross-species reactivity does not itself alter theclassification of an antigen-binding module as a “specific” binder. Incertain embodiments, an antigen-binding module (e.g., ABM1, ABM2 and/orABM3) that specifically binds to a human antigen has cross-speciesreactivity with one or more non-human mammalian species, e.g., a primatespecies (including but not limited to one or more of Macacafascicularis, Macaca mulatta, and Macaca nemestrina) or a rodentspecies, e.g., Mus musculus. In other embodiments, the antigen-bindingmodule (e.g., ABM1, ABM2 and/or ABM3) does not have cross-speciesreactivity.

Subject: The term “subject” includes human and non-human animals.Non-human animals include all vertebrates, e.g., mammals andnon-mammals, such as non-human primates, sheep, dog, cow, chickens,amphibians, and reptiles. Except when noted, the terms “patient” or“subject” are used herein interchangeably.

Tandem of VH Domains: The term “a tandem of VH domains (or VHs)” as usedherein refers to a string of VH domains, consisting of multiple numbersof identical VH domains of an antibody. Each of the VH domains, exceptthe last one at the end of the tandem, has its C-terminus connected tothe N-terminus of another VH domain with or without a linker. A tandemhas at least 2 VH domains, and in particular embodiments of the MBMs has3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VH can be producedby joining the encoding nucleic acids of each VH domain in a desiredorder using recombinant methods with or without a linker (e.g., asdescribed in Section 7.3.3) that enables them to be made as a singlepolypeptide chain. The N-terminus of the first VH domain in the tandemis defined as the N-terminus of the tandem, while the C-terminus of thelast VH domain in the tandem is defined as the C-terminus of the tandem.

Tandem of VL Domains: The term “a tandem of VL domains (or VLs)” as usedherein refers to a string of VL domains, consisting of multiple numbersof identical VL domains of an antibody. Each of the VL domains, exceptthe last one at the end of the tandem, has its C-terminus connected tothe N-terminus of another VL with or without a linker. A tandem has atleast 2 VL domains, and in particular embodiments an MBM has 3, 4, 5, 6,7, 8, 9, or 10 VL domains. The tandem of VL can be produced by joiningthe encoding nucleic acids of each VL domain in a desired order usingrecombinant methods with or without a linker (e.g., as described inSection 7.3.3) that enables them to be made as a single polypeptidechain. The N-terminus of the first VL domain in the tandem is defined asthe N-terminus of the tandem, while the C-terminus of the last VL domainin the tandem is defined as the C-terminus of the tandem.

Target Antigen: By “target antigen” as used herein is meant the moleculethat is bound non-covalently, reversibly and specifically by an antigenbinding domain.

Tetravalent: The term “tetravalent” as used herein in the context of anantigen-binding molecule (e.g., a TBM) refers to an antigen-bindingmolecule that has four antigen-binding domains. Tetravalent TBMs of thedisclosure generally have two antigen-binding domains that bind to thesame antigen (e.g., BCMA) and two antigen-binding domains that each bindto a separate antigen (e.g., a component of a TCR complex and either CD2or a TAA). Examples of tetravalent TBMs are shown schematically in FIGS.1Q-1S.

Therapeutically effective amount: A “therapeutically effective amount”refers to an amount effective, at dosages and for periods of timenecessary, to achieve a desired therapeutic result.

Treat, Treatment, Treating: As used herein, the terms “treat”,“treatment” and “treating” refer to the reduction or amelioration of theprogression, severity and/or duration of a disease or disorder (e.g., aproliferative disorder), or the amelioration of one or more symptoms(e.g., one or more discernible symptoms) of a disorder resulting fromthe administration of one or more MBMs (e.g., TBMs) of the disclosure.In some embodiments, the terms “treat”, “treatment” and “treating” referto the amelioration of at least one measurable physical parameter of adisorder, such as growth of a tumor, not necessarily discernible by thepatient. In other embodiments the terms “treat”, “treatment” and“treating” refer to the inhibition of the progression of a disorder,either physically by, e.g., stabilization of a discernible symptom,physiologically by, e.g., stabilization of a physical parameter, orboth. In some embodiments, the terms “treat”, “treatment” and “treating”can refer to the reduction or stabilization of tumor size or cancerouscell count.

Trispecific binding molecules: The term “trispecific binding molecules”or “TBMs” refers to molecules that specifically bind to three antigensand comprise three or more antigen-binding domains. The TBMs of thedisclosure comprise at least one antigen-binding domain which isspecific for BCMA, at least one antigen-binding domain which is specificfor a component of a TCR complex, and at least one antigen-bindingdomain which is specific for CD2 or a TAA. The antigen-binding domainscan each independently be an antibody fragment (e.g., scFv, Fab,nanobody), a ligand, or a non-antibody derived binder (e.g.,fibronectin, Fynomer, DARPin). Representative TBMs are illustrated inFIG. 1 . TBMs can comprise one, two, three, four or even morepolypeptide chains. For example, the TBM illustrated in FIG. 1Mcomprises a single polypeptide chain comprising three scFvs connected byABM linkers one a single polypeptide chain. The TBM illustrated in FIG.1K comprises two polypeptide chains comprising three scFvs connected by,inter alia, an Fc domain. The TBM illustrated in FIG. 1J comprises threepolypeptide chains forming an scFv, a ligand, and a Fab connected by,inter alia, an Fc domain. The TBM illustrated in FIG. 10 comprises fourpolypeptide chains forming three Fabs connected by, inter alia, an Fcdomain. The TBM illustrated in FIG. 1U comprises 6 polypeptide chainsforming four Fabs and two scFvs connected by, inter alia, an Fc domain.

Trivalent: The term “trivalent” as used herein in the context of anantigen-binding molecule (e.g., a TBM) refers to an antigen-bindingmolecule that has three antigen-binding domains. The TBMs of thedisclosure are trispecific and specifically bind to BCMA, a component ofa TCR complex, and CD2 or a TAA. Accordingly, the trivalent TBMs havethree antigen-binding domains that each bind to a different antigen.Examples of trivalent TBMs are shown schematically in FIGS. 1B-1V.

Tumor: The term “tumor” is used interchangeably with the term “cancer”herein, e.g., both terms encompass solid and liquid, e.g., diffuse orcirculating, tumors. As used herein, the term “cancer” or “tumor”includes premalignant, as well as malignant cancers and tumors.

Tumor-Associated Antigen: The term “tumor-associated antigen” or “TAA”refers to a molecule (typically a protein, carbohydrate, lipid or somecombination thereof) that is expressed on the surface of a cancer cell,either entirely or as a fragment (e.g., MHC/peptide), and which isuseful for the preferential targeting of a pharmacological agent to thecancer cell. In some embodiments, a TAA is a marker expressed by bothnormal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on Bcells. In some embodiments, a TAA is a cell surface molecule that isoverexpressed in a cancer cell in comparison to a normal cell, forinstance, 1-fold over expression, 2-fold overexpression, 3-foldoverexpression or more in comparison to a normal cell. In someembodiments, a TAA is a cell surface molecule that is inappropriatelysynthesized in the cancer cell, for instance, a molecule that containsdeletions, additions or mutations in comparison to the moleculeexpressed on a normal cell. In some embodiments, a TAA will be expressedexclusively on the cell surface of a cancer cell, entirely or as afragment (e.g., MHC/peptide), and not synthesized or expressed on thesurface of a normal cell. Accordingly, the term “TAA” encompassesantigens that are specific to cancer cells, sometimes referred to astumor-specific antigens (“TSAs”). Although BCMA has features of atumor-associated antigen, the terms “tumor-associated antigen” and “TAA”are used throughout the disclosure to refer to molecules other thanBCMA.

Variable region: By “variable region” or “variable domain” as usedherein is meant the region of an immunoglobulin that comprises one ormore Ig domains substantially encoded by any of the VK, VA, and/or VHgenes that make up the kappa, lambda, and heavy chain immunoglobulingenetic loci respectively, and contains the CDRs that confer antigenspecificity. A “variable heavy domain” can pair with a “variable lightdomain” to form an antigen binding domain (“ABD”) or antigen-bindingmodule (“ABM”). In addition, each variable domain comprises threehypervariable regions (“complementary determining regions,” “CDRs”)(CDR-H1, CDR-H2, CDR-H3 for the variable heavy domain and CDR-L1,CDR-L2, CDR-L3 for the variable light domain) and four framework (FR)regions, arranged from amino-terminus to carboxy-terminus in thefollowing order: FR₁-CDR1-FR2-CDR2-FR3-CDR3-FR4.

Vector: The term “vector” is intended to refer to a polynucleotidemolecule capable of transporting another polynucleotide to which it hasbeen linked. One type of vector is a “plasmid”, which refers to acircular double stranded DNA loop into which additional DNA segments canbe ligated. Another type of vector is a viral vector, where additionalDNA segments can be ligated into the viral genome. Certain vectors arecapable of autonomous replication in a host cell into which they areintroduced (e.g., bacterial vectors having a bacterial origin ofreplication and episomal mammalian vectors). Other vectors (e.g.,non-episomal mammalian vectors) can be integrated into the genome of ahost cell upon introduction into the host cell, and thereby arereplicated along with the host genome. Moreover, certain vectors arecapable of directing the expression of genes to which they are operablylinked. Such vectors are referred to herein as “recombinant expressionvectors” (or simply, “expression vectors”). In general, expressionvectors of utility in recombinant DNA techniques are often in the formof plasmids. In the present specification, “plasmid” and “vector” can beused interchangeably as the plasmid is the most commonly used form ofvector. However, the disclosure is intended to include such other formsof expression vectors, such as viral vectors (e.g., replicationdefective retroviruses, adenoviruses and adeno-associated viruses),which serve equivalent functions.

VH: The term “VH” refers to the variable region of an immunoglobulinheavy chain of an antibody, including the heavy chain of an Fv, scFv,dsFv or Fab.

VL: The term “VL” refers to the variable region of an immunoglobulinlight chain, including the light chain of an Fv, scFv, dsFv or Fab.

VH-VL or VH-VL Pair: In reference to a VH-VL pair, whether on the samepolypeptide chain or on different polypeptide chains, the terms “VH-VL”and “VH-VL pair” are used for convenience and are not intended to conveyany particular orientation, unless the context dictates otherwise. Thus,a scFv comprising a “VH-VL” or “VH-VL pair” can have the VH and VLdomains in any orientation, for example the VH N-terminal to the VL orthe VL N-terminal to the VH.

7.2. Antigen Binding Modules

Typically, one or more ABMs of the MBMs comprise immunoglobulin-basedantigen-binding domains, for example the sequences of antibody fragmentsor derivatives. These antibody fragments and derivatives typicallyinclude the CDRs of an antibody and can include larger fragments andderivatives thereof, e.g., Fabs, scFabs, Fvs, and scFvs.

Immunoglobulin-based ABMs can comprise modifications to frameworkresidues within a VH and/or a VL, e.g. to improve the properties of aMBM containing the ABM. For example, framework modifications can be madeto decrease immunogenicity of a MBM. One approach for making suchframework modifications is to “back-mutate” one or more frameworkresidues of the ABM to a corresponding germline sequence. Such residuescan be identified by comparing framework sequences to germline sequencesfrom which the ABM is derived. To “match” framework region sequences todesired germline configuration, residues can be “back-mutated” to acorresponding germline sequence by, for example, site-directedmutagenesis. MBMs having such “back-mutated” ABMs are intended to beencompassed by the disclosure.

Another type of framework modification involves mutating one or moreresidues within a framework region, or even within one or more CDRregions, to remove T-cell epitopes to thereby reduce potentialimmunogenicity of a MBM. This approach is also referred to as“deimmunization” and is described in further detail in U.S. PatentPublication No. 20030153043 by Carr et al.

ABMs can also be modified to have altered glycosylation, which can beuseful, for example, to increase the affinity of a MBM for one or moreof its antigens. Such carbohydrate modifications can be accomplished by,for example, altering one or more sites of glycosylation within an ABMsequence. For example, one or more amino acid substitutions can be madethat result in elimination of one or more variable region frameworkglycosylation sites to thereby eliminate glycosylation at that site.Such aglycosylation may increase the affinity of the MBM for an antigen.Such an approach is described in, e.g., U.S. Pat. Nos. 5,714,350 and6,350,861 by Co et al.

7.2.1. Immunoglobulin Based Modules

7.2.1.1. Fabs

In certain aspects, an ABM is a Fab domain. Fab domains can be producedby proteolytic cleavage of immunoglobulin molecules, using enzymes suchas papain, or through recombinant expression. Fab domains typicallycomprise a CH1 domain attached to a VH domain which pairs with a CLdomain attached to a VL domain.

In a wild-type immunoglobulin, the VH domain is paired with the VLdomain to constitute the Fv region, and the CH1 domain is paired withthe CL domain to further stabilize the binding module. A disulfide bondbetween the two constant domains can further stabilize the Fab domain.

For the MBMs (e.g., TBMs) of the disclosure, it is advantageous to useFab heterodimerization strategies to permit the correct association ofFab domains belonging to the same ABM and minimize aberrant pairing ofFab domains belonging to different ABMs. For example, the Fabheterodimerization strategies shown in Table 1 below can be used:

TABLE 1 Fab Heterodimerization Strategies Name STRATEGY VH CH1 VL CLREFERENCE F1 CrossMabCH WT CL domain WT CH1 Schaefer et al., 1-CL domain2011, Cancer Cell 2011; 20:472-86; PMID:22014573. F2 orthogonal 39K, 62EH172A, 1R, 38D, L135Y, Lewis et al., 2014, Fab F174G (36F) S176W NatBiotechnol VHVRD1CH1 32:191-8 CRD2 - VLVRD1CλC RD2 F3 orthogonal 39Y WT38R WT Lewis et al., 2014, Fab Nat Biotechnol VHVRD2CH1 32:191-8 wt -VLVRD2Cλwt F4 TCR CαCβ 39K TCRCα 38D TCR Cβ Wu et al., 2015, MAbs7:364-76 F5 CR3 WT T192E WT N137K, Golay at al., 2016, J S114A Immunol196:3199- 211. F6 MUT4 WT L143Q, WT V133T, Golay at al., 2016, J S188VS176V Immunol 196:3199- 211. F7 DuetMab WT F126C WT S121C Mazor et al.,2015, MAbs 7:377-89; Mazor et al., 2015, MAbs 7:461-669.

Accordingly, in certain embodiments, correct association between the twopolypeptides of a Fab is promoted by exchanging the VL and VH domains ofthe Fab for each other or exchanging the CH1 and CL domains for eachother, e.g., as described in WO 2009/080251.

Correct Fab pairing can also be promoted by introducing one or moreamino acid modifications in the CH1 domain and one or more amino acidmodifications in the CL domain of the Fab and/or one or more amino acidmodifications in the VH domain and one or more amino acid modificationsin the VL domain. The amino acids that are modified are typically partof the VH:VL and CH1:CL interface such that the Fab componentspreferentially pair with each other rather than with components of otherFabs.

In one embodiment, the one or amino acid modifications are limited tothe conserved framework residues of the variable (VH, VL) and constant(CH1, CL) domains as indicated by the Kabat numbering of residues.Almagro, 2008, Frontiers In Bioscience 13:1619-1633 provides adefinition of the framework residues on the basis of Kabat, Chothia, andIMGT numbering schemes.

In one embodiment, the modifications introduced in the VH and CH1 and/orVL and CL domains are complementary to each other. Complementarity atthe heavy and light chain interface can be achieved on the basis ofsteric and hydrophobic contacts, electrostatic/charge interactions orany combination of the variety of interactions. The complementaritybetween protein surfaces is broadly described in the literature in termsof lock and key fit, knob into hole, protrusion and cavity, donor andacceptor etc., all implying the nature of structural and chemical matchbetween the two interacting surfaces.

In one embodiment, the one or more introduced modifications introduce anew hydrogen bond across the interface of the Fab components. In oneembodiment, the one or more introduced modifications introduce a newsalt bridge across the interface of the Fab components. Exemplarysubstitutions are described in WO 2014/150973 and WO 2014/082179.

In some embodiments, the Fab domain comprises a 192E substitution in theCH1 domain and 114A and 137K substitutions in the CL domain, whichintroduces a salt-bridge between the CH1 and CL domains (see, Golay etal., 2016, J Immunol 196:3199-211).

In some embodiments, the Fab domain comprises a 143Q and 188Vsubstitutions in the CH1 domain and 113T and 176V substitutions in theCL domain, which serves to swap hydrophobic and polar regions of contactbetween the CH1 and CL domain (see, Golay et al., 2016, J Immunol196:3199-211).

In some embodiments, the Fab domain can comprise modifications in someor all of the VH, CH1, VL, CL domains to introduce orthogonal Fabinterfaces which promote correct assembly of Fab domains (Lewis et al.,2014 Nature Biotechnology 32:191-198). In an embodiment, 39K, 62Emodifications are introduced in the VH domain, H172A, F174Gmodifications are introduced in the CH1 domain, 1R, 38D, (36F)modifications are introduced in the VL domain, and L135Y, S176Wmodifications are introduced in the CL domain. In another embodiment, a39Y modification is introduced in the VH domain and a 38R modificationis introduced in the VL domain.

Fab domains can also be modified to replace the native CH1:CL disulfidebond with an engineered disulfide bond, thereby increasing theefficiency of Fab component pairing. For example, an engineereddisulfide bond can be introduced by introducing a 126C in the CH1 domainand a 121C in the CL domain (see, Mazor et al., 2015, MAbs 7:377-89).

Fab domains can also be modified by replacing the CH1 domain and CLdomain with alternative domains that promote correct assembly. Forexample, Wu et al., 2015, MAbs 7:364-76, describes substituting the CH1domain with the constant domain of the a T cell receptor andsubstituting the CL domain with the _(R) domain of the T cell receptor,and pairing these domain replacements with an additional charge-chargeinteraction between the VL and VH domains by introducing a 38Dmodification in the VL domain and a 39K modification in the VH domain.

ABMs can comprise a single chain Fab fragment, which is a polypeptideconsisting of an antibody heavy chain variable domain (VH), an antibodyconstant domain 1 (CH1), an antibody light chain variable domain (VL),an antibody light chain constant domain (CL) and a linker. In someembodiments, the antibody domains and the linker have one of thefollowing orders in N-terminal to C-terminal direction: a)VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1 ord) VL-CH1-linker-VH-CL. The linker can be a polypeptide of at least 30amino acids, e.g., between 32 and 50 amino acids. The single chain Fabdomains are stabilized via the natural disulfide bond between the CLdomain and the CH1 domain.

In an embodiment, the antibody domains and the linker in the singlechain Fab fragment have one of the following orders in N-terminal toC-terminal direction: a) VH-CH1-linker-VL-CL, or b) VL-CL-linker-VH-CH1.In some cases, VL-CL-linker-VH-CH1 is used.

In another embodiment, the antibody domains and the linker in the singlechain Fab fragment have one of the following orders in N-terminal toC-terminal direction: a) VH-CL-linker-VL-CH1 or b) VL-CH1-linker-VH-CL.

Optionally in the single chain Fab fragment, additionally to the naturaldisulfide bond between the CL-domain and the CH1 domain, also theantibody heavy chain variable domain (VH) and the antibody light chainvariable domain (VL) are disulfide stabilized by introduction of adisulfide bond between the following positions: i) heavy chain variabledomain position 44 to light chain variable domain position 100, ii)heavy chain variable domain position 105 to light chain variable domainposition 43, or iii) heavy chain variable domain position 101 to lightchain variable domain position 100 (numbering according to EU index ofKabat).

Such further disulfide stabilization of single chain Fab fragments isachieved by the introduction of a disulfide bond between the variabledomains VH and VL of the single chain Fab fragments. Techniques tointroduce unnatural disulfide bridges for stabilization for a singlechain Fv are described e.g. in WO 94/029350, Rajagopal et al., 1997,Prot. Engin. 10:1453-59; Kobayashi et al., 1998, Nuclear Medicine &Biology, 25:387-393; and Schmidt, et al., 1999, Oncogene 18:1711-1721.In one embodiment, the optional disulfide bond between the variabledomains of the single chain Fab fragments is between heavy chainvariable domain position 44 and light chain variable domain position100. In one embodiment, the optional disulfide bond between the variabledomains of the single chain Fab fragments is between heavy chainvariable domain position 105 and light chain variable domain position 43(numbering according to EU index of Kabat).

-   -   7.2.1.2. scFvs

Single chain Fv or “scFv” antibody fragments comprise the VH and VLdomains of an antibody in a single polypeptide chain, are capable ofbeing expressed as a single chain polypeptide, and retain thespecificity of the intact antibody from which it is derived. Generally,the scFv polypeptide further comprises a polypeptide linker between theVH and VL domain that enables the scFv to form the desired structure fortarget binding. Examples of linkers suitable for connecting the VH andVL chains of an scFV are the ABM linkers identified in Section 7.3.3,for example any of the linkers designated L1 through L54.

Unless specified, as used herein an scFv can have the VL and VH variableregions in either order, e.g., with respect to the N-terminal andC-terminal ends of the polypeptide, the scFv can comprise VL-linker-VHor can comprise VH-linker-VL.

To create an scFv-encoding nucleic acid, the VH and VL-encoding DNAfragments are operably linked to another fragment encoding a linker,e.g., encoding any of the ABM linkers described in Section 7.3.3 (suchas the amino acid sequence (Gly4^(˜)Ser)3 (SEQ ID NO: 1)), such that theVH and VL sequences can be expressed as a contiguous single-chainprotein, with the VL and VH regions joined by the flexible linker (seee.g., Bird et al., 1988, Science 242:423-426; Huston et al., 1988, Proc.Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., 1990, Nature348:552-554).

7.2.1.3. Other immunoglobulin-based modules

MBMs can also comprise ABMs having an immunoglobulin format which isother than Fab or scFv, for example Fv, dsFv, (Fab′)2, a single domainantibody (SDAB), a VH or VL domain, or a camelid VHH domain (also calleda nanobody).

An ABM can be a single domain antibody composed of a single VH or VLdomain which exhibits sufficient affinity to the target. In someembodiments, the single domain antibody is a camelid VHH domain (see,e.g., Riechmann, 1999, Journal of Immunological Methods 231:25-38; WO94/04678).

7.2.2. Non-Immunoglobulin Based Modules

In certain embodiments, one or more of the ABMs are derived fromnon-antibody scaffold proteins (including, but not limited to, designedankyrin repeat proteins (DARPins), Avimers (short for aviditymultimers), Anticalin/Lipocalins, Centyrins, Kunitz domains, Adnexins,Affilins, Affitins (also known as Nonfitins), Knottins, Pronectins,Versabodies, Duocalins, and Fynomers), ligands, receptors, cytokines orchemokines.

Non-immunoglobulin scaffolds that can be used in the MBMs include thoselisted in Tables 3 and 4 of Mintz and Crea, 2013, BioprocessInternational 11(2):40-48; in FIG. 1 , Table 1 and Figure I ofVazquez-Lombardi et al., 2015, Drug Discovery Today 20(10):1271-83; inTable 1 and Box 2 of Skrlec et al., 2015, Trends in Biotechnology33(7):408-18. The contents of Tables 3 and 4 of Mintz and Crea, 2013,Bioprocess International 11(2):40-48; in FIG. 1 , Table 1 and Figure Iof Vazquez-Lombardi et al., 2015, Drug Discovery Today 20(10):1271-83;in Table 1 and Box 2 of Skrlec et al., 2015, Trends in Biotechnology33(7):408-18 (collectively, “Scaffold Disclosures”). In a particularembodiment, the Scaffold Disclosures are incorporated by reference forwhat they disclose relating to Adnexins. In another embodiment, theScaffold Disclosures are incorporated by reference for what theydisclose relating to Avimers. In another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to Affibodies. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to Anticalins. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to DARPins. In yet another embodiment, the Scaffold Disclosuresare incorporated by reference for what they disclose relating to Kunitzdomains. In yet another embodiment, the Scaffold Disclosures areincorporated by reference for what they disclose relating to Knottins.In yet another embodiment, the Scaffold Disclosures are incorporated byreference for what they disclose relating to Pronectins. In yet anotherembodiment, the Scaffold Disclosures are incorporated by reference forwhat they disclose relating to Nanofitins. In yet another embodiment,the Scaffold Disclosures are incorporated by reference for what theydisclose relating to Affilins. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to Adnectins. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to ABDs. In yet another embodiment, the Scaffold Disclosuresare incorporated by reference for what they disclose relating toAdhirons. In yet another embodiment, the Scaffold Disclosures areincorporated by reference for what they disclose relating to Affimers.In yet another embodiment, the Scaffold Disclosures are incorporated byreference for what they disclose relating to Alphabodies. In yet anotherembodiment, the Scaffold Disclosures are incorporated by reference forwhat they disclose relating to Armadillo Repeat Proteins. In yet anotherembodiment, the Scaffold Disclosures are incorporated by reference forwhat they disclose relating to Atrimers/Tetranectins. In yet anotherembodiment, the Scaffold Disclosures are incorporated by reference forwhat they disclose relating to Obodies/OB-folds. In yet anotherembodiment, the Scaffold Disclosures are incorporated by reference forwhat they disclose relating to Centyrins. In yet another embodiment, theScaffold Disclosures are incorporated by reference for what theydisclose relating to Repebodies. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to Anticalins. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to Atrimers. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to bicyclic peptides. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to cys-knots. In yet another embodiment, the ScaffoldDisclosures are incorporated by reference for what they discloserelating to Fn3 scaffolds (including Adnectins, Centryrins, Pronectins,and Tn3).

In an embodiment, an ABM can be a designed ankyrin repeat protein(“DARPin”). DARPins are antibody mimetic proteins that typically exhibithighly specific and high-affinity target protein binding. They aretypically genetically engineered and derived from natural ankyrinproteins and consist of at least three, usually four or five repeatmotifs of these proteins. Their molecular mass is about 14 or 18 kDa(kilodaltons) for four- or five-repeat DARPins, respectively. Examplesof DARPins can be found, for example in U.S. Pat. No. 7,417,130.Multispecific binding molecules comprising DARPin binding modules andimmunoglobulin-based binding modules are disclosed in, for example, U.S.Publication No. 2015/0030596 Al.

In another embodiment, an ABM can be an Affibody. An Affibody is wellknown and refers to affinity proteins based on a 58 amino acid residueprotein domain, derived from one of the IgG binding domain ofstaphylococcal protein A.

In another embodiment, an ABM can be an Anticalin. Anticalins are wellknown and refer to another antibody mimetic technology, where thebinding specificity is derived from Lipocalins. Anticalins can also beformatted as dual targeting protein, called Duocalins.

In another embodiment, an ABM can be a Versabody. Versabodies are wellknown and refer to another antibody mimetic technology. They are smallproteins of 3-5 kDa with >15% cysteines, which form a high disulfidedensity scaffold, replacing the hydrophobic core of typical proteins.

Other non-immunoglobulin ABMs include “A” domain oligomers (also knownas Avimers) (see for example, U.S. Patent Application Publication Nos.2005/0164301, 2005/0048512, and 2004/017576), Fn3 based proteinscaffolds (see for example, U.S. Patent Application Publication2003/0170753), VASP polypeptides, Avian pancreatic polypeptide (aPP),Tetranectin (based on CTLD3), Affililin (based onγB-crystallin/ubiquitin), Knottins, SH3 domains, PDZ domains,Tendamistat, Neocarzinostatin, Protein A domains, Lipocalins,Transferrin, or Kunitz domains. In one aspect, ABMs useful in theconstruction of the MBMs comprise fibronectin-based scaffolds asexemplified in WO 2011/130324.

7.3. Connectors

It is contemplated that the MBMs can in some instances include pairs ofABMs or ABM chains (e.g., the VH-CH1 or VL-CL component of a Fab)connected directly to one another, e.g., as a fusion protein without alinker. For example, the MBMs comprise connector moieties linkingindividual ABMs or ABM chains. The use of connector moieties can improvetarget binding, for example by increasing flexibility of the ABMs withina MBM and thus reducing steric hindrance. The ABMs can be connected toone another through, for example, Fc domains (each Fc domainrepresenting a pair of associated Fc regions) and/or ABM linkers. Theuse of Fc domains will typically require the use of hinge regions asconnectors of the ABMs or ABM chains for optimal antigen binding. Thus,the term “connector” encompasses, but is not limited to, Fc regions, Fcdomains, hinge regions, and ABM linkers.

Connectors can be selected or modified to, for example, increase ordecrease the biological half-life of a MBM of the disclosure. Forexample, to decrease biological half-life, one or more amino acidmutations can be introduced into a CH₂—CH3 domain interface region of anFc-hinge fragment such that a MBM comprising the fragment has impairedStaphylococcyl Protein A (SpA) binding relative to native Fc-hingedomain SpA binding. This approach is described in further detail in U.S.Pat. No. 6,165,745 by Ward et al. Alternatively, a MBM can be modifiedto increase its biological half-life. For example, one or more of thefollowing mutations can be introduced: T252L, T254S, T256F, as describedin U.S. Pat. No. 6,277,375 to Ward. Alternatively, to increase thebiological half-life, a MBM can be altered within a CH1 or CL region tocontain a salvage receptor binding epitope taken from two loops of a CH2domain of an Fc region of an IgG, as described in U.S. Pat. Nos.5,869,046 and 6,121,022 by Presta et al.

Examples of Fc domains (formed by the pairing of two Fc regions), hingeregions and ABM linkers are described in Sections 7.3.1, 7.3.2, and7.3.3, respectively.

7.3.1. Fc domains

The MBMs (e.g., TBMs) can include an Fc domain derived from any suitablespecies. In one embodiment, the Fc domain is derived from a human Fcdomain.

The Fc domain can be derived from any suitable class of antibody,including IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG(including subclasses IgG1, IgG2, IgG3 and IgG4), and IgM. In oneembodiment, the Fc domain is derived from IgG1, IgG2, IgG3 or IgG4. Inone embodiment, the Fc domain is derived from IgG1. In one embodiment,the Fc domain is derived from IgG4.

The Fc domain comprises two polypeptide chains, each referred to as aheavy chain Fc region. The two heavy chain Fc regions dimerize to createthe Fc domain. The two Fc regions within the Fc domain can be the sameor different from one another. In a native antibody the Fc regions aretypically identical, but for the purpose of producing multispecificbinding molecules, e.g., the TBMs of the disclosure, the Fc regionsmight advantageously be different to allow for heterodimerization, asdescribed in Section 7.3.1.5 below.

Typically each heavy chain Fc region comprises or consists of two orthree heavy chain constant domains.

In native antibodies, the heavy chain Fc region of IgA, IgD and IgG iscomposed of two heavy chain constant domains (CH2 and CH₃) and that ofIgE and IgM is composed of three heavy chain constant domains (CH2, CH3and CH4). These dimerize to create an Fc domain.

In the present disclosure, the heavy chain Fc region can comprise heavychain constant domains from one or more different classes of antibody,for example one, two or three different classes.

In one embodiment, the heavy chain Fc region comprises CH₂ and CH3domains derived from IgG1. An exemplary sequence of a heavy chain Fcregion derived from human IgG1 is given in SEQ ID NO:872:

(SEQ ID NO: 872) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP.

In some embodiments, a MBM of the disclosure comprises a Fc region whoseamino acid sequence comprises the amino acid sequence of SEQ ID NO:872modified with one or more of the substitutions described in Section7.3.1 and its subparts.

In one embodiment, the heavy chain Fc region comprises CH₂ and CH3domains derived from IgG2.

In one embodiment, the heavy chain Fc region comprises CH₂ and CH3domains derived from IgG3.

In one embodiment, the heavy chain Fc region comprises CH₂ and CH3domains derived from IgG4.

In one embodiment, the heavy chain Fc region comprises a CH4 domain fromIgM. The IgM CH4 domain is typically located at the C-terminus of theCH3 domain.

In one embodiment, the heavy chain Fc region comprises CH₂ and CH3domains derived from IgG and a CH4 domain derived from IgM.

It will be appreciated that the heavy chain constant domains for use inproducing a heavy chain Fc region for the MBMs of the present disclosurecan include variants of the naturally occurring constant domainsdescribed above. Such variants can comprise one or more amino acidvariations compared to wild type constant domains. In one example theheavy chain Fc region of the present disclosure comprises at least oneconstant domain that varies in sequence from the wild type constantdomain. It will be appreciated that the variant constant domains can belonger or shorter than the wild type constant domain. For example, thevariant constant domains are at least 60% identical or similar to a wildtype constant domain. In another example the variant constant domainsare at least 70% identical or similar. In another example the variantconstant domains are at least 75% identical or similar. In anotherexample the variant constant domains are at least 80% identical orsimilar. In another example the variant constant domains are at least85% identical or similar. In another example the variant constantdomains are at least 90% identical or similar. In another example thevariant constant domains are at least 95% identical or similar. Inanother example the variant constant domains are at least 99% identicalor similar. Exemplary Fc variants are described in Sections 7.3.1.1through 7.3.1.5, infra.

IgM and IgA occur naturally in humans as covalent multimers of thecommon H₂L2 antibody unit. IgM occurs as a pentamer when it hasincorporated a J-chain, or as a hexamer when it lacks a J-chain. IgAoccurs as monomer and dimer forms. The heavy chains of IgM and IgApossess an 18 amino acid extension to the C-terminal constant domain,known as a tailpiece. The tailpiece includes a cysteine residue thatforms a disulfide bond between heavy chains in the polymer, and isbelieved to have an important role in polymerization. The tailpiece alsocontains a glycosylation site. In certain embodiments, the MBMs of thepresent disclosure do not comprise a tailpiece.

The Fc domains that are incorporated into the MBMs (e.g., TBMs) of thepresent disclosure can comprise one or more modifications that alter oneor more functional properties of the proteins, such as serum half-life,complement fixation, Fc receptor binding, and/or antigen-dependentcellular cytotoxicity. Furthermore, a MBM can be chemically modified(e.g., one or more chemical moieties can be attached to the MBM) or bemodified to alter its glycosylation, again to alter one or morefunctional properties of the MBM.

Effector function of an antibody molecule includes complement-mediatedeffector function, which is mediated by, for example, binding of the Clcomponent of the complement to the antibody. Activation of complement isimportant in the opsonization and direct lysis of pathogens. Inaddition, it stimulates the inflammatory response by recruiting andactivating phagocytes to the site of complement activation. Effectorfunction includes Fc receptor (FcR)-mediated effector function, whichcan be triggered upon binding of the constant domains of an antibody toan Fc receptor (FcR). Antigen-antibody complex-mediated crosslinking ofFc receptors on effector cell surfaces triggers a number of importantand diverse biological responses including engulfment and destruction ofantibody-coated particles, clearance of immune complexes, lysis ofantibody-coated target cells by killer cells (called antibody-dependentcell-mediated cytotoxicity, or ADCC), release of inflammatory mediators,placental transfer and control of immunoglobulin production.

Fc regions can be altered by replacing at least one amino acid residuewith a different amino acid residue to alter the effector functions. Forexample, one or more amino acids can be replaced with a different aminoacid residue such that the Fc region has an altered affinity for aneffector ligand. The effector ligand to which affinity is altered canbe, for example, an Fc receptor or the Cl component of complement. Thisapproach is described in, e.g., U.S. Pat. Nos. 5,624,821 and 5,648,260,both by Winter et al. Modified Fc regions can also alter C1q bindingand/or reduce or abolish complement dependent cytotoxicity (CDC). Thisapproach is described in, e.g., U.S. Pat. No. 6,194,551 by Idusogie etal. Modified Fc regions can also alter the ability of an Fc region tofix complement. This approach is described in, e.g., the PCT PublicationWO 94/29351 by Bodmer et al. Allotypic amino acid residues include, butare not limited to, constant region of a heavy chain of the IgG1, IgG2,and IgG3 subclasses as well as constant region of a light chain of thekappa isotype as described by Jefferis et al., 2009, MAbs, 1:332-338.

Fc regions can also be modified to “silence” the effector function, forexample, to reduce or eliminate the ability of a MBM to mediate antibodydependent cellular cytotoxicity (ADCC) and/or antibody dependentcellular phagocytosis (ADCP). This can be achieved, for example, byintroducing a mutation in an Fc region. Such mutations have beendescribed in the art: LALA and N297A (Strohl, 2009, Curr. Opin.Biotechnol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol.181: 6664-69; Strohl, supra). Examples of silent Fc IgG1 antibodiescomprise the so-called LALA mutant comprising L234A and L235A mutationin the IgG1 Fc amino acid sequence. Another example of a silent IgG1antibody comprises the D265A mutation. Another silent IgG1 antibodycomprises the so-called DAPA mutant comprising D265A and P329A mutationsin the IgG1 Fc amino acid sequence. Another silent IgG1 antibodycomprises the N297A mutation, which results inaglycosylated/non-glycosylated antibodies.

Fc regions can be modified to increase the ability of a MBM containingthe Fc region to mediate antibody dependent cellular cytotoxicity (ADCC)and/or antibody dependent cellular phagocytosis (ADCP), for example, bymodifying one or more amino acid residues to increase the affinity ofthe MBM for an activating Fcγ receptor, or to decrease the affinity ofthe MBM for an inhibatory Fcγ receptor. Human activating Fcγ receptorsinclude FcγRIa, FcγRIIa, FcγRIIIa, and FcγRIIIb, and human inhibitoryFcγ receptor includes FcγRIIb. This approach is described in, e.g., thePCT Publication WO0/42072 by Presta. Moreover, binding sites on humanIgG1 for FcγRI, FcγRII, FcγRIII and FcRn have been mapped and variantswith improved binding have been described (see Shields et al., J. Biol.Chem. 276:6591-6604, 2001). Optimization of Fc-mediated effectorfunctions of monoclonal antibodies such as increased ADCC/ADCP functionhas been described (see Stroh, 2009, Current Opinion in Biotechnology20:685-691). Mutations that can enhance ADCC/ADCP function include oneor more mutations selected from G236A, S239D, F243L, P2471, D280H,K290S, R292P, S298A, S298D, S298V, Y300L, V3051, A330L, 1332E, E333A,K334A, A339D, A339Q, A339T, and P396L (all positions by EU numbering).

Fc regions can also be modified to increase the ability of a MBM tomediate ADCC and/or ADCP, for example, by modifying one or more aminoacids to increase the affinity of the MBM for an activating receptorthat would typically not recognize the parent MBM, such as FcαRI. Thisapproach is described in, e.g., Borrok et al., 2015, mAbs. 7(4):743-751.

Accordingly, in certain aspects, the MBMs of the present disclosure caninclude Fc domains with altered effector function such as, but notlimited to, binding to Fc-receptors such as FcRn or leukocyte receptors(for example, as described above or in Section 7.3.1.1), binding tocomplement (for example as described above or in Section 7.3.1.2),modified disulfide bond architecture (for example as described above orin Section 7.3.1.3), or altered glycosylation patterns (for example asdescribed above or in Section 7.3.1.4). The Fc domains can also bealtered to include modifications that improve manufacturability ofasymmetric MBMs, for example by allowing heterodimerization, which isthe preferential pairing of non-identical Fc regions over identical Fcregions. Heterodimerization permits the production of MBMs in whichdifferent ABMs are connected to one another by an Fc domain containingFc regions that differ in sequence. Examples of heterodimerizationstrategies are exemplified in Section 7.3.1.5 (and subsections thereof).

It will be appreciated that any of the modifications described inSections 7.3.1.1 through 7.3.1.5 can be combined in any suitable mannerto achieve the desired functional properties and/or combined with othermodifications to alter the properties of the MBMs. In some embodiments,a MBM comprises a IgG1 Fc domain having a mutation at 1, 2, 3, 4, 5, 6,or more than 6 of positions 233, 234, 235, 236, 237, 239, 265, 266, 267,268, 269, 297, 299, 322, 327, 328, 329, 330, 331 and 332 (EU numbering).For example, a MBM can comprise an IgG1 sequence of SEQ ID NO:872 with amutation at 1, 2, 3, 4, 5, 6, or more than 6 of positions 233, 234, 235,236, 237, 239, 265, 266, 267, 268, 269, 297, 299, 322, 327, 328, 329,330, 331 and 332

7.3.1.1. Fc Domains with Altered FcR Binding

The Fc domains of the MBMs (e.g., TBMs) can show altered binding to oneor more Fc-receptors (FcRs) in comparison with the corresponding nativeimmunoglobulin. The binding to any particular Fc-receptor can beincreased or decreased. In one embodiment, the Fc domain comprises oneor more modifications which alter its Fc-receptor binding profile.

Human cells can express a number of membrane bound FcRs selected fromFcaR, FccR, FcγR, FcRn and glycan receptors. Some cells are also capableof expressing soluble (ectodomain) FcR (Fridman et al., 1993, JLeukocyte Biology 54: 504-512). FcγR can be further divided by affinityof IgG binding (high/low) and biological effect (activating/inhibiting).Human FcγRl is widely considered to be the sole ‘high affinity’ receptorwhilst all of the others are considered as medium to low. FcγRIIb is thesole receptor with ‘inhibitory’ functionality by virtue of itsintracellular ITIM motif whilst all of the others are considered as‘activating’ by virtue of ITAM motifs or pairing with the commonFcγR--ychain. FcγRIIIb is also unique in that although activatory itassociates with the cell via a GPI anchor. In total, humans express six“standard” FcγRs: FcγRl, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, andFcγRIIIb. In addition to these sequences there are a large number ofsequence or allotypic variants spread across these families. Some ofthese have been found to have important functional consequence and soare sometimes considered to be receptor sub-types of their own. Examplesinclude FcγRIIH^(H134R), FcγRIIb^(I190T), FcγRIIIa^(F158V),FcγRIIIb^(NA1), FcγRIIIb^(NA2), and FcγRIII^(SH). Each receptor sequencehas been shown to have different affinities for the 4 sub-classes ofIgG: IgG1, IgG2, IgG3 and IgG4 (Bruhns, 1993, Blood 113:3716-3725).Other species have somewhat different numbers and functionality of FcγR,with the mouse system being the best studied to date and comprising of 4FcγR, FcγRl FcγRIIb FcγRIII FcγRIV (Bruhns, 2012, Blood 119:5640-5649).Human FcγRI on cells is normally considered to be ‘occupied’ bymonomeric IgG in normal serum conditions due to its affinity forIgG1/IgG3/IgG4 (about 10⁻⁸ M) and the concentration of these IgG inserum (about 10 mg/ml). Hence cells bearing FcγRl on their surface areconsidered to be capable for “screening” or “sampling” of theirantigenic environment vicariously through the bound polyspecific IgG.The other receptors having lower affinities for IgG sub-classes (in therange of about 10⁻⁵-10⁻⁷ M) are normally considered to be “unoccupied.”The low affinity receptors are hence inherently sensitive to thedetection of and activation by antibody involved immune complexes. Theincreased Fc density in an antibody immune complex results in increasedfunctional affinity of binding avidity to low affinity FcγR. This hasbeen demonstrated in vitro using a number of methods (Shields et al.,2001, J Biol Chem 276(9):6591-6604; Lux et al., 2013, J Immunol190:4315-4323). It has also been implicated as being one of the primarymodes of action in the use of anti-RhD to treat ITP in humans (Crow,2008, Transfusion Medicine Reviews 22:103-116).

Many cell types express multiple types of FcγR and so binding of IgG orantibody immune complex to cells bearing FcγR can have multiple andcomplex outcomes depending upon the biological context. Most simply,cells can either receive an activatory, inhibitory or mixed signal. Thiscan result in events such as phagocytosis (e.g., macrophages andneutrophils), antigen processing (e.g., dendritic cells), reduced IgGproduction (e.g., B-cells) or degranulation (e.g., neutrophils, mastcells). There are data to support that the inhibitory signal fromFcγRIIb can dominate that of activatory signals (Proulx, 2010, ClinicalImmunology 135:422-429).

There are a number of useful Fc substitutions that can be made to alterbinding to one or more of the FcγR receptors. Substitutions that resultin increased binding as well as decreased binding can be useful. Forexample, it is known that increased binding to FcγRIIIa generallyresults in increased ADCC (antibody dependent cell-mediatedcytotoxicity; the cell-mediated reaction where nonspecific cytotoxiccells that express FcγRs recognize bound antibody on a target cell andsubsequently cause lysis of the target cell). Similarly, decreasedbinding to FcγRIIb (an inhibitory receptor) can be beneficial as well insome circumstances. Amino acid substitutions that find use in thepresent disclosure include those listed in US 2006/0024298 (particularlyFIG. 41 ), US 2006/0121032, US 2006/0235208, US 2007/0148170, and US2019/0100587. Particular variants that find use include, but are notlimited to, 236A, 239D, 239E, 332E, 332D, 239D, 332E, 267D, 267E, 328F,267E, 328F, 236A, 332E, 239D,332E, 330Y, 239D, 332E, 330L, 243A, 243L,264A, 264V, 299T, 265A, 297A, 329A, 265N, 297D, 329G, and 265E, 297Q,329S.

FcRn has a crucial role in maintaining the long half-life of IgG in theserum of adults and children. The receptor binds IgG in acidifiedvesicles (pH<6.5) protecting the IgG molecule from degradation, and thenreleasing it at the higher pH of 7.4 in blood.

FcRn is unlike leukocyte Fc receptors, and instead, has structuralsimilarity to MHC class I molecules. It is a heterodimer composed of aβ₂-microglobulin chain, non-covalently attached to a membrane-boundchain that includes three extracellular domains. One of these domains,including a carbohydrate chain, together with β₂-microglobulin interactswith a site between the CH2 and CH3 domains of Fc. The interactionincludes salt bridges made to histidine residues on IgG that arepositively charged at pH<6.5. At higher pH, the His residues lose theirpositive charges, the FcRn-IgG interaction is weakened and IgGdissociates.

In one embodiment, a MBM comprises an Fc domain that binds to humanFcRn.

In one embodiment, the Fc domain has an (e.g., one or two) Fc regionscomprising a histidine residue at position 310, and in some cases alsoat position 435. These histidine residues are important for human FcRnbinding. In one embodiment, the histidine residues at positions 310 and435 are native residues, i.e., positions 310 and 435 are not modified.Alternatively, one or both of these histidine residues can be present asa result of a modification.

The MBMs can comprise one or more Fc regions that alter Fc binding toFcRn. The altered binding can be increased binding or decreased binding.

In one embodiment, the MBM comprises an Fc domain in which at least one(and optionally both) Fc regions comprises one or more modificationssuch that it binds to FcRn with greater affinity and avidity than thecorresponding native immunoglobulin.

Fc substitutions that increase binding to the FcRn receptor and increaseserum half life are described in US 2009/0163699, including, but notlimited to, 434S, 434A, 428L, 308F, 2591, 428L, 434S, 2591/308F,4361/428L, 4361 or V, 434S, 436V, 428L and 2591/308F, 428L.

In one embodiment, the Fc region is modified by substituting thethreonine residue at position 250 with a glutamine residue (T250Q).

In one embodiment, the Fc region is modified by substituting themethionine residue at position 252 with a tyrosine residue (M252Y)

In one embodiment, the Fc region is modified by substituting the serineresidue at position 254 with a threonine residue (S254T).

In one embodiment, the Fc region is modified by substituting thethreonine residue at position 256 with a glutamic acid residue (T256E).

In one embodiment, the Fc region is modified by substituting thethreonine residue at position 307 with an alanine residue (T307A).

In one embodiment, the Fc region is modified by substituting thethreonine residue at position 307 with a proline residue (T307P).

In one embodiment, the Fc region is modified by substituting the valineresidue at position 308 with a cysteine residue (V308C).

In one embodiment, the Fc region is modified by substituting the valineresidue at position 308 with a phenylalanine residue (V308F).

In one embodiment, the Fc region is modified by substituting the valineresidue at position 308 with a proline residue (V308P).

In one embodiment, the Fc region is modified by substituting theglutamine residue at position 311 with an alanine residue (Q311A).

In one embodiment, the Fc region is modified by substituting theglutamine residue at position 311 with an arginine residue (Q311R).

In one embodiment, the Fc region is modified by substituting themethionine residue at position 428 with a leucine residue (M428L).

In one embodiment, the Fc region is modified by substituting thehistidine residue at position 433 with a lysine residue (H433K).

In one embodiment, the Fc region is modified by substituting theasparagine residue at position 434 with a phenylalanine residue (N434F).

In one embodiment, the Fc region is modified by substituting theasparagine residue at position 434 with a tyrosine residue (N434Y).

In one embodiment, the Fc region is modified by substituting themethionine residue at position 252 with a tyrosine residue, the serineresidue at position 254 with a threonine residue, and the threonineresidue at position 256 with a glutamic acid residue(M252Y/S254T/T256E).

In one embodiment, the Fc region is modified by substituting the valineresidue at position 308 with a proline residue and the asparagineresidue at position 434 with a tyrosine residue (V308P/N434Y).

In one embodiment, the Fc region is modified by substituting themethionine residue at position 252 with a tyrosine residue, the serineresidue at position 254 with a threonine residue, the threonine residueat position 256 with a glutamic acid residue, the histidine residue atposition 433 with a lysine residue and the asparagine residue atposition 434 with a phenylalanine residue(M252Y/S254T/T256E/H433K/N434F).

It will be appreciated that any of the modifications listed above can becombined to alter FcRn binding.

In one embodiment, the MBM comprises an Fc domain in which one or bothFc regions comprise one or more modifications such that the Fc domainbinds to FcRn with lower affinity and avidity than the correspondingnative immunoglobulin.

In one embodiment, the Fc region comprises any amino acid residue otherthan histidine at position 310 and/or position 435.

The MBM can comprise an Fc domain in which one or both Fc regionscomprise one or more modifications which increase its binding toFcγRIIb. FcγRIIb is the only inhibitory receptor in humans and the onlyFc receptor found on B cells.

In one embodiment, the Fc region is modified by substituting the prolineresidue at position 238 with an aspartic acid residue (P238D).

In one embodiment, the Fc region is modified by substituting theglutamic acid residue at position 258 with an alanine residue (E258A).

In one embodiment, the Fc region is modified by substituting the serineresidue at position 267 with an alanine residue (S267A).

In one embodiment, the Fc region is modified by substituting the serineresidue at position 267 with a glutamic acid residue (S267E).

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 328 with a phenylalanine residue (L328F).

In one embodiment, the Fc region is modified by substituting theglutamic acid residue at position 258 with an alanine residue and theserine residue at position 267 with an alanine residue (E258A/S267A).

In one embodiment, the Fc region is modified by substituting the serineresidue at position 267 with a glutamic acid residue and the leucineresidue at position 328 with a phenylalanine residue (S267E/L328F).

It will be appreciated that any of the modifications listed above can becombined to increase FcγRIIb binding.

In one embodiment, MBMs are provided comprising Fc domains which displaydecreased binding to FcγR.

In one embodiment, an MBM comprises an Fc domain in which one or both Fcregions comprise one or more modifications that decrease Fc binding toFcγR.

The Fc domain can be derived from IgG1.

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 234 with an alanine residue (L234A).

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 235 with an alanine residue (L235A).

In one embodiment, the Fc region is modified by substituting the glycineresidue at position 236 with an arginine residue (G236R).

In one embodiment, the Fc region is modified by substituting theasparagine residue at position 297 with an alanine residue (N297A) or aglutamine residue (N297Q).

In one embodiment, the Fc region is modified by substituting the serineresidue at position 298 with an alanine residue (S298A).

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 328 with an arginine residue (L328R).

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 234 with an alanine residue and the leucine residueat position 235 with an alanine residue (L234A/L235A).

In one embodiment, the Fc region is modified by substituting thephenylalanine residue at position 234 with an alanine residue and theleucine residue at position 235 with an alanine residue (F234A/L235A).

In one embodiment, the Fc region is modified by substituting the glycineresidue at position 236 with an arginine residue and the leucine residueat position 328 with an arginine residue (G236R/L328R).

In one embodiment, the Fc region is modified by substituting theaspartate residue at position 265 with an alanine residue, theasparagine residue at position 297 with an alanine residue and theproline residue at position 329 with an alanine residue(D265A/N297A/P329A).

In one embodiment, the Fc region is modified by substituting theaspartate residue at position 265 with an asparagine residue, theasparagine residue at position 297 with an aspartate residue and theproline residue at position 329 with a glycine residue(D265N/N297D/P329G).

In one embodiment, the Fc region is modified by substituting theaspartate residue at position 265 with a glutamate residue, theasparagine residue at position 297 with an glutamine residue and theproline residue at position 329 with a serine residue(D265E/N297Q/P329S).

It will be appreciated that any of the modifications listed above can becombined to decrease FcγR binding.

In one embodiment, a MBM comprises an Fc domain in which one or both Fcregions comprise one or more modifications that decrease Fc binding toFcγRIIIa without affecting the Fc's binding to FcγRII.

In one embodiment, the Fc region is modified by substituting the serineresidue at position 239 with an alanine residue (S239A).

In one embodiment, the Fc region is modified by substituting theglutamic acid residue at position 269 with an alanine residue (E269A).

In one embodiment, the Fc region is modified by substituting theglutamic acid residue at position 293 with an alanine residue (E293A).

In one embodiment, the Fc region is modified by substituting thetyrosine residue at position 296 with a phenylalanine residue (Y296F).

In one embodiment, the Fc region is modified by substituting the valineresidue at position 303 with an alanine residue (V303A).

In one embodiment, the Fc region is modified by substituting the alanineresidue at position 327 with a glycine residue (A327G).

In one embodiment, the Fc region is modified by substituting the lysineresidue at position 338 with an alanine residue (K338A).

In one embodiment, the Fc region is modified by substituting theaspartic acid residue at position 376 with an alanine residue (D376A).

It will be appreciated that any of the modifications listed above can becombined to decrease FcγRIIIa binding.

Fc region variants with decreased FcR binding can be referred to as“FcγR ablation variants,” “FcγR silencing variants” or “Fc knock out(FcKO or KO)” variants. For some therapeutic applications, it isdesirable to reduce or remove the normal binding of an Fc domain to oneor more or all of the Fcγ receptors (e.g., FcγR1, FcγRIIa, FcγRIIb,FcγRIIIa) to avoid additional mechanisms of action. That is, forexample, in many embodiments, particularly in the use of MBMs that bindCD3 monovalently, it is generally desirable to ablate FcγRIIIa bindingto eliminate or significantly reduce ADCC activity. In some embodiments,at least one of the Fc regions of the MBMs described herein comprisesone or more Fcγ receptor ablation variants. In some embodiments, both ofthe Fc regions comprise one or more Fcγ receptor ablation variants.These ablation variants are depicted in Table 2, and each can beindependently and optionally included or excluded, with some aspectsutilizing ablation variants selected from the group consisting ofG236R/L328R, E233P/L234V/L235A/G236del/S239K,E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G,E233P/L234V/L235A/G236del/S267K/A327G E233P/L234V/L235A/G236del,D265A/N297A/P329A, D265N/N297D/P329G, and D265E/N297Q/P329S (“del”connotes a deletion, e.g., G236del refers to a deletion of the glycineat position 236). It should be noted that the ablation variantsreferenced herein ablate FcγR binding but generally not FcRn binding.

TABLE 2 Ablation Variants Variant Variant(s), cont. G236R P329K S239GA330L S239K A330S/P331S S239Q I332K S239R I332R V266D V266D/A327Q S267KV266D/P329K S267R S267R/A327Q H268K S267R/P329K E269R G236R/L328R 299RE233P/L234V/L235A/G236del/S239K 299K E233P/L234V/L235A/G236del/S267KK322A E233P/L234V/L235A/G236del/S239K/A327G A327GE233P/L234V/L235A/G236del/S267K/A327G A327L E233P/L234V/L235A/G236delA327N S239K/S267K A327Q 267K/P329K L328E D265A/N297A/P329A L328RD265N/N297D/P329G P329A D265E/N297Q/P329S P329H

In some embodiments, the MBMs of the present disclosure comprises afirst Fc region and a second Fc region. In some embodiments, the firstFc region and/or the second Fc region can comprise the followingmutations: E233P, L234V, L235A, G236del, and S267K.

The Fc domain of human IgG1 has the highest binding to the Fcγreceptors, and thus ablation variants can be used when the constantdomain (or Fc domain) in the backbone of the heterodimeric antibody isIgG1.

Alternatively, or in addition to ablation variants in an IgG1background, mutations at the glycosylation position 297, e.g.,substituting the asparagine residue at position 297 with an alanineresidue (N297A) or a glutamine residue (N297Q), can significantly ablatebinding to FcγRIIIa, for example. Human IgG2 and IgG4 have naturallyreduced binding to the Fcy receptors, and thus those backbones can beused with or without the ablation variants.

7.3.1.2. Fc Domains with Altered Complement Binding

An MBM (e.g., TBM) can comprise an Fc domain in which one or both Fcregions comprises one or more modifications that alter Fc binding tocomplement. Altered complement binding can be increased binding ordecreased binding.

In one embodiment, the Fc region comprises one or more modificationswhich decrease its binding to C1q. Initiation of the classicalcomplement pathway starts with binding of hexameric C1q protein to theCH2 domain of antigen bound IgG and IgM.

In one embodiment, the MBM comprises an Fc domain in which one or bothFc regions comprises one or more modifications to decrease Fc binding toC1q.

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 234 with an alanine residue (L234A).

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 235 with an alanine residue (L235A).

In one embodiment, the Fc region is modified by substituting the leucineresidue at position 235 with a glutamic acid residue (L235E).

In one embodiment, the Fc region is modified by substituting the glycineresidue at position 237 with an alanine residue (G237A).

In one embodiment, the Fc region is modified by substituting the lysineresidue at position 322 with an alanine residue (K322A).

In one embodiment, the Fc region is modified by substituting the prolineresidue at position 331 with an alanine residue (P331A).

In one embodiment, the Fc region is modified by substituting the prolineresidue at position 331 with a serine residue (P331S).

In one embodiment, a MBM comprises an Fc domain derived from IgG4. IgG4has a naturally lower complement activation profile than IgG1, but alsoweaker binding of FcγR. Thus, in one embodiment, the MBM comprises anIgG4 Fc domain and also comprises one or more modifications thatincrease FcγR binding.

It will be appreciated that any of the modifications listed above can becombined to reduce C1q binding.

7.3.1.3. Fc Domains with Altered Disulfide Architecture

An MBM (e.g., TBM) can include an Fc domain comprising one or moremodifications to create and/or remove a cysteine residue. Cysteineresidues have an important role in the spontaneous assembly of Fc-basedmultispecific binding molecules, by forming disulfide bridges betweenindividual pairs of polypeptide monomers. Thus, by altering the numberand/or position of cysteine residues, it is possible to modify thestructure of the MBM to produce a protein with improved therapeuticproperties.

A MBM can comprise an Fc domain in which one or both Fc regions, e.g.,both Fc regions, comprise a cysteine residue at position 309. In oneembodiment, the cysteine residue at position 309 is created by amodification, e.g., for an Fc domain derived from IgG1, the leucineresidue at position 309 is substituted with a cysteine residue (L3090),for an Fc domain derived from IgG2, the valine residue at position 309is substituted with a cysteine residue (V3090).

In one embodiment, the Fc region is modified by substituting the valineresidue at position 308 with a cysteine residue (V3080).

In one embodiment, two disulfide bonds in the hinge region are removedby mutating a core hinge sequence CPPC (SEQ ID NO: 2) to SPPS (SEQ IDNO: 3).

7.3.1.4. Fc Domains with Altered Glycosylation

In certain aspects, MBMs (e.g., TBMs) with improved manufacturabilityare provided that comprise fewer glycosylation sites than acorresponding immunoglobulin. These proteins have less complex posttranslational glycosylation patterns and are thus simpler and lessexpensive to manufacture.

In one embodiment, a glycosylation site in the CH2 domain is removed bysubstituting the asparagine residue at position 297 with an alanineresidue (N297A) or a glutamine residue (N297Q). In addition to improvedmanufacturability, these aglycosyl mutants also reduce FcγR binding asdescribed herein above.

In some embodiments, a MBM can be made that has an altered type ofglycosylation, such as a hypofucosylated antibody having reduced amountsof fucosyl residues or an antibody having increased bisecting GlcNacstructures. Such altered glycosylation patterns have been demonstratedto increase the ADCC ability of antibodies. Such carbohydratemodifications can be accomplished by, for example, expressing a MBM in ahost cell with altered glycosylation machinery. Cells with alteredglycosylation machinery have been described in the art and can be usedas host cells in which to express MBMs to thereby produce MBM withaltered glycosylation. For example, EP 1,176,195 by Hang et al.describes a cell line with a functionally disrupted FUT8 gene, whichencodes a fucosyl transferase, such that antibodies expressed in such acell line exhibit hypofucosylation. PCT Publication WO3/035835 by Prestadescribes a variant CHO cell line, Lecl3 cells, with reduced ability toattach fucose to Asn(297)-linked carbohydrates, also resulting inhypofucosylation of antibodies expressed in that host cell (see alsoShields et al., 2002, J. Biol. Chem. 277:26733-26740). PCT PublicationWO 99/54342 by Umana et al. describes cell lines engineered to expressglycoprotein-modifying glycosyl transferases (e.g., beta(1,4)-Nacetylglucosaminyltransferase III (GnTIII)) such that antibodiesexpressed in the engineered cell lines exhibit increased bisectingGlcNac structures which results in increased ADCC activity of theantibodies (see also Umana et al., Nat. Biotech. 17:176-180, 1999).

7.3.1.5. Fc Heterodimerization

Many multispecific molecule formats entail dimerization between two Fcregions that, unlike a native immunoglobulin, are operably linked tonon-identical antigen-binding domains (or portions thereof, e.g., a VHor VH-CH1 of a Fab). Inadequate heterodimerization of two Fc regions toform an Fc domain has always been an obstacle for increasing the yieldof desired multispecific molecules and represents challenges forpurification. A variety of approaches available in the art can be usedin for enhancing dimerization of Fc regions that might be present in theMBMs (e.g., TBMs) of the disclosure, for example as disclosed in EP1870459A1; U.S. Pat. Nos. 5,582,996, 5,731,168, 5,910,573, 5,932,448;6,833,441; 7,183,076; U.S. Patent Application Publication No.2006204493A1; and PCT Publication No. WO2009/089004A1.

The present disclosure provides MBMs (e.g., TBMs) comprising Fcheterodimers, i.e., Fc domains comprising heterologous, non-identical Fcregions. Heterodimerization strategies are used to enhance dimerizationof Fc regions operably linked to different ABMs (or portions thereof,e.g., a VH or VH-CH1 of a Fab) and reduce dimerization of Fc regionsoperably linked to the same ABM or portion thereof. Typically, each Fcregion in the Fc heterodimer comprises a CH3 domain of an antibody. TheCH3 domains are derived from the constant region of an antibody of anyisotype, class or subclass, and in some cases, of IgG (IgG1, IgG2, IgG3and IgG4) class, as described in the preceding section.

Typically, the MBMs comprise other antibody fragments in addition to CH3domains, such as, CH1 domains, CH2 domains, hinge domain, VH domain(s),VL domain(s), CDR(s), and/or antigen-binding fragments described herein.In some embodiments, the two hetero-polypeptides are two heavy chainsforming a bispecific or multispecific molecules. Heterodimerization ofthe two different heavy chains at CH3 domains give rise to the desiredantibody or antibody-like molecule, while homodimerization of identicalheavy chains will reduce yield of the desired antibody or molecule. Inan exemplary embodiment, the two or more hetero-polypeptide chainscomprise two chains comprising CH3 domains and forming the molecules ofany of the multispecific molecule formats described above of the presentdisclosure. In an embodiment, the two hetero-polypeptide chainscomprising CH3 domains comprise modifications that favor heterodimericassociation of the polypeptides, relative to unmodified chains. Variousexamples of modification strategies are provided below in Table 3 andSections 7.3.1.5.1 to 7.3.1.5.7.

TABLE 3 Fc Heterodimerization Strategies NO. STRATEGY CH3 DOMAIN 1 CH3DOMAIN 2 REFERENCES Fc 1 knobs-into-holes T366Y Y407T Ridgway et al.,1996, (Y-T) Protein Eng 9:617-21 Fc 2 knobs-into-holes S354C, T366WY349C, T366S, Atwell et al., 1997, J (CW-CSAV) L368A, Y407V Mol Biol.270(1):26- 35; Merchant et al., 1998, Nat Biotechnol 16:677-681 Fc 3HA-TF S364H, F405A Y349T, T394F Moore et al., 2011, MAbs 3(6):546-57 Fc4 ZW1 (VYAV-VLLW) T350V, L351Y, T350V, T366L, Von Kreudenstein et F405A,Y407V K392L, T394W al., 2013, MAbs 5:646-54 Fc 5 CH3 charge pairs K392D,K409D E356K, D399K Gunasekaran et al., (DD-KK) 2010, J Biol Chem285:19637-46 Fc 6 IgG1 hingE,CH3 IgG1: D221E, IgG1: D221R, Strop et al.,2012, J charge pairs (EEE- P228E, L368E P228R, K409R Mol Biol 420:204-19RRR) Fc 7 IgG2 hingE,CH3 IgG2: C223E, IgG2: C223R, Strop et al., 2012, Jcharge pairs (EEE- P228E, L368E E225R, P228R, Mol Biol 420:204-19 RRRR)K409R Fc 8 EW-RVT K360E, K409W, Q347R, D399V, Choi eta!., 2013, F405TMol Cancer Ther 12:2748-59 Fc 9 EW-RVTS-S K360E, K409W, Q347R, D399V,Choi eta!., 2015, Y349C F405T, S354C Mol Immunol 65:377-83 Fc 10Biclonic 366K (+351K) 351D or E or D at Geuijen et al., 2014, 349, 368,349, or Journal of Clinical 349 + 355 Oncology 32:suppl:560 Fc 11DuoBody (L-R) F405L K409R Labrijn et al., 2013, Proc Natl Acad Sci USA110:5145-50 Fc 12 SEEDbody IgG/A chimera IgG/A chimera Davis et al.,2010, Protein Eng Des Sel 23:195-202 Fc 13 BEAT residues from residuesfrom Moretti et al., 2013, TCRα interface TCRβ interface BMC Proceedings7(Suppl 6):09 Fc 14 7.8.60 (DMA- K360D, D399M, E345R, Q347R, Lea ver-Feyet al., RRW) Y407A T366V, K409V Structure 24:641-51 Fc 15 20.8.34 (SYMV-Y349S, K370Y, E356G, E357D, Lea ver-Fey et al., GDQA) T366M, K409VS364Q, Y407A Structure 24:641-51 Fc 16 Skew variant 12757 None noneFigure 34 of US 2016/0355600 Fc 17 Skew variant 12758 L368D, K370S S364KFigure 34 of US 2016/0355600 Fc 18 Skew variant 12759 L368D, K370SS364K, E357L Figure 34 of US 2016/0355600 Fc 19 Skew variant 12760L368D, K370S S364K, E357Q Figure 34 of US 2016/0355600 Fc 20 Skewvariant 12761 T411E, K360E, D401K Figure 34 of US Q362E 2016/0355600 Fc21 Skew variant 12496 L368E, K370S S364K Figure 34 of US 2016/0355600 Fc22 Skew variant 12511 K370S S364K Figure 34 of US 2016/0355600 Fc 23Skew variant 12840 L368E, K370S S364K, E357Q Figure 34 of US2016/0355600 Fc 24 Skew variant 12841 K370S S364K, E357Q Figure 34 of US2016/0355600 Fc 25 Skew variant 12894 L368E, K370S S364K Figure 34 of US2016/0355600 Fc 26 Skew variant 12895 K370S S364K Figure 34 of US2016/0355600 Fc 27 Skew variant 12896 L368E, K370S S364K, E357Q Figure34 of US 2016/0355600 Fc 28 Skew variant 12901 K370S S364K, E357Q FIG.34 of US 2016/0355600 Fc 29 pl_ISO(-) I199T, N203D, FIG. 31 of US K274Q,R355Q, 2016/0355600 N384S, K392N, V397M, Q419E, DEL447 Fc 30pl_(-)_lsosteric_A N208D, Q295E, FIG. 31 of US N384D, Q418E,2016/0355600 N421D Fc31 pl_(-)_isosteric_B N208D, Q295E, FIG. 31 of USQ418E, N421D 2016/0355600 Fc 32 pl_ISO(+RR) Q196K, I199T, FIG. 31 of USP217R, P228R, 2016/0355600 N276K Fc 33 pl_ISO(+) Q196K, I199T, FIG. 31of US N276K 2016/0355600 Fc 34 pl_(+) isosteric_A E269Q, E272Q, FIG. 31of US E283Q, E357Q, 2016/0355600 Fc 35 pl_(+)_isosteric_B E269Q, E272Q,FIG. 31 of US E283Q 2016/0355600 Fc 36 PL(+) E269Q, E272Q FIG. 31 of USisosteric_E269Q, 2016/0355600 E272Q Fc 37 pl_(+)_isosteric_E2 E269Q,E283Q FIG. 31 of US 69Q, E283Q 2016/0355600 Fc 38 pl_(+) E272Q, E283QFIG. 31 of US isosteric_E2720, 2016/0355600 E283Q Fc 39pl_(+)_isosteric_E2 E269Q FIG. 31 of US 69Q 2016/0355600 Fc 40Heterodimerization F405A T394F FIG. 30A of US 2016/0355600 Fc 41Heterodimerization S364D Y349K FIG. 30A of US 2016/0355600 Fc 42Heterodimerization S364E L368K FIG. 30A of US 2016/0355600 Fc 43Heterodimerization S364E Y349K FIG. 30A of US 2016/0355600 Fc 44Heterodimerization S364F K370G FIG. 30A of US 2016/0355600 Fc 45Heterodimerization S364H Y349K FIG. 30A of US 2016/0355600 Fc 46Heterodimerization S364H Y349T FIG. 30A of US 2016/0355600 Fc 47Heterodimerization S364Y K370G FIG. 30A of US 2016/0355600 Fc 48Heterodimerization T411K K370E FIG. 30A of US 2016/0355600 Fc 49Heterodimerization V397S, F405A T394F FIG. 30A of US 2016/0355600 Fc 50Heterodimerization K370R, T411K K370E, T411E FIG. 30A of US 2016/0355600Fc 51 Heterodimerization L351E, S364D Y349K, L351K FIG. 30A of US2016/0355600 Fc 52 Heterodimerization L351E, S364E Y349K, L351K FIG. 30Aof US 2016/0355600 Fc 53 Heterodimerization L351E, T366D L351K, T366KFIG. 30A of US 2016/0355600 Fc 54 Heterodimerization P395T,V397S, T394FFIG. 30A of US F405A 2016/0355600 Fc 55 Heterodimerization S364D, K370GS364Y, K370R FIG. 30A of US 2016/0355600 Fc 56 Heterodimerization S364D,T394F Y349K, F405A FIG. 30A of US 2016/0355600 Fc 57 HeterodimerizationS364E, F405A Y349K, T394F FIG. 30A of US 2016/0355600 Fc 58Heterodimerization S364E, F405S Y349K, T394Y FIG. 30A of US 2016/0355600Fc 59 Heterodimerization S364E, T411E Y349K.D401K FIG. 30A of US2016/0355600 Fc 60 Heterodimerization S364H.D401K Y349T, T411E FIG. 30Aof US 2016/0355600 Fc 61 Heterodimerization S364H, F405A Y349T, T394FFIG. 30A of US 2016/0355600 Fc 62 Heterodimerization S364H, T394F Y349T,F405A FIG. 30A of US 2016/0355600 Fc 63 Heterodimerization Y349C, S364EY349K, S354C FIG. 30A of US 2016/0355600 Fc 64 Heterodimerization L351E,S364D, Y349K, L351K, FIG. 30A of US F405A T394F 2016/0355600 Fc 65Heterodimerization L351K, S364H, Y349T, L351E, FIG. 30A of US D401KT411E 2016/0355600 Fc 66 Heterodimerization S364E, T411E, Y349K, T394F,FIG. 30A of US F405A D401K 2016/0355600 Fc 67 HeterodimerizationS364H.D401K, Y349T, T394F, FIG. 30A of US F405A T411E 2016/0355600 Fc 68Heterodimerization S364H, F405A, Y349T, T394F, FIG. 30A of US T411ED401K 2016/0355600 Fc 69 Heterodimerization T411E, K360E, D401K FIG. 30Cof US N390D 2016/0355600 Fc 70 Heterodimerization T411E, Q362E, D401KFIG. 30C of US N390D 2016/0355600 Fc 71 Heterodimerization T411E, Q347RD401K, K360D FIG. 30C of US 2016/0355600 Fc 72 Heterodimerization T411E,Q347R D401K, K360E FIG. 30C of US 2016/0355600 Fc 73 HeterodimerizationT411E, K360 D401K, Q347K FIG. 30C of US 2016/0355600 Fc 74Heterodimerization T411E, K360D D401K, Q347R FIG. 30C of US 2016/0355600Fc 75 Heterodimerization T411E, K360E D401K, Q347K FIG. 30C of US2016/0355600 Fc 76 Heterodimerization T411E, K360E D401K, Q347R FIG. 30Cof US 2016/0355600 Fc 77 Heterodimerization T411E, S364K D401K, K370SFIG. 30C of US 2016/0355600 Fc 78 Heterodimerization T411E, K370S D401K,S364K FIG. 30C of US 2016/0355600 Fc 79 Heterodimerization Q347E E357QFIG. 30C of US 2016/0355600 Fc 80 Heterodimerization Q347E E357Q, Q362KFIG. 30C of US 2016/0355600 Fc 81 Heterodimerization K360D, Q362E Q347RFIG. 30C of US 2016/0355600 Fc 82 Heterodimerization K360D, Q362E D401KFIG. 30C of US 2016/0355600 Fc 83 Heterodimerization K360D, Q362E Q347R,D401K FIG. 30C of US 2016/0355600 Fc 84 Heterodimerization K360E, Q362EQ347R FIG. 30C of US 2016/0355600 Fc 85 Heterodimerization K360E, Q362ED401K FIG. 30C of US 2016/0355600 Fc 86 Heterodimerization K360E, Q362EQ347R, D401K FIG. 30C of US 2016/0355600 Fc 87 Heterodimerization Q362E,N390D D401K FIG. 30C of US 2016/0355600 Fc 88 Heterodimerization Q347E,K360D D401N FIG. 30C of US 2016/0355600 Fc 89 Heterodimerization K360DQ347R, N390K FIG. 30C of US 2016/0355600 Fc 90 Heterodimerization K360DN390K, D401N FIG. 30C of US 2016/0355600 Fc 91 Heterodimerization K360EY349H FIG. 30C of US 2016/0355600 Fc 92 Heterodimerization K370S, Q347ES364K FIG. 30C of US 2016/0355600 Fc 93 Heterodimerization K370S, E357LS364K FIG. 30C of US 2016/0355600 Fc 94 Heterodimerization K370S, E357QS364K FIG. 30C of US 2016/0355600 Fc 95 Heterodimerization K370S, Q347E,S364K FIG. 30C of US E357L 2016/0355600 Fc 96 Heterodimerization K370S,Q347E, S364K FIG. 30C of US E357Q 2016/0355600 Fc 97 HeterodimerizationL368D, K370S, S364K FIG. 30D of US Q347E 2016/0355600 Fc 98Heterodimerization L368D, K370S, S364K FIG. 30D of US E357L 2016/0355600Fc 99 Heterodimerization L368D, K370S, S364K FIG. 30D of US E357Q2016/0355600 Fc Heterodimerization L368D, K370S, S364K FIG. 30D of US100 Q347E, E357L 2016/0355600 Fc Heterodimerization L368D, K370S, S364KFIG. 30D of US 101 Q347E, E357Q 2016/0355600 Fc HeterodimerizationL368E, K370S, S364K FIG. 30D of US 102 Q347E 2016/0355600 FcHeterodimerization L368E, K370S, S364K FIG. 30D of US 103 E357L2016/0355600 Fc Heterodimerization L368E, K370S, S364K FIG. 30D of US104 E357Q 2016/0355600 Fc Heterodimerization L368E, K370S, S364K FIG.30D of US 105 Q347E, E357L 2016/0355600 Fc Heterodimerization L368E,K370S, S364K FIG. 30D of US 106 Q347E, E357Q 2016/0355600 FcHeterodimerization L368D, K370T, S364K FIG. 30D of US 107 Q347E2016/0355600 Fc Heterodimerization L368D, K370T, S364K FIG. 30D of US108 E357L 2016/0355600 Fc Heterodimerization L368D, K370T, S364K FIG.30D of US 109 E357Q 2016/0355600 Fc Heterodimerization L368D, K370T,S364K FIG. 30D of US 110 Q347E, E357L 2016/0355600 Fc HeterodimerizationL368D, K370T, S364K FIG. 30D of US 111 Q347E, E357Q 2016/0355600 FcHeterodimerization L368E, K370T, S364K FIG. 30D of US 112 Q347E2016/0355600 Fc Heterodimerization L368E, K370T, S364K FIG. 30D of US113 E357L 2016/0355600 Fc Heterodimerization L368E, K370T, S364K FIG.30D of US 114 E357Q 2016/0355600 Fc Heterodimerization L368E, K370T,S364K FIG. 30D of US 115 Q347E, E357L 2016/0355600 Fc HeterodimerizationL368E, K370T, S364K FIG. 30D of US 116 Q347E, E357Q 2016/0355600 FcHeterodimerization T411E, Q362E D401K, T411K FIG. 30D of US 1172016/0355600 Fc Heterodimerization T411E, N390D D401K, T411K FIG. 30D ofUS 118 2016/0355600 Fc Heterodimerization T411E, Q362E D401R, T411R FIG.30D of US 119 2016/0355600 Fc Heterodimerization T411E, N390D D401R,T411R FIG. 30D of US 120 2016/0355600 Fc Heterodimerization Y407T T366YFIG. 30D of US 121 2016/0355600 Fc Heterodimerization F405A T394W FIG.30D of US 122 2016/0355600 Fc Heterodimerization T366Y, F405A T394W,Y407T FIG. 30D of US 123 2016/0355600 Fc Heterodimerization T366S,L368A, T366W FIG. 30D of US 124 Y407V 2016/0355600 Fc HeterodimerizationT366S, L368A, T366W, S354C FIG. 30D of US 125 Y407V, Y349C 2016/0355600Fc Heterodimerization K392D, K409D E356K.D399K FIG. 30E of US 1262016/0355600 Fc Heterodimerization K370D, K392D, E356K, E357K, FIG. 30Eof US 127 K409D D399K 2016/0355600 Fc Heterodimerization I199T, N203D,Q196K, L99T, FIG. 30E of US 128 K247Q,R355Q, P217R, P228R, 2016/0355600N384S, K392N, N276K V397M, Q419E, K447 Fc Heterodimerization I199T,N203D, Q196K, L99T, FIG. 30E of US 129 K247Q,R355Q, N276K 2016/0355600N384S, K392N, V397M, Q419E, K447 Fc Heterodimerization N384S, K392N,N276K FIG. 30E of US 130 V397M, Q419E 2016/0355600 Fc HeterodimerizationD221E, P228E, D221R, P228R, FIG. 30E of US 131 L368E K409R 2016/0355600Fc Heterodimerization C220E, P228E, C220R, E224R, FIG. 30E of US 132L368E P228R, K409R 2016/0355600 Fc Heterodimerization F405L K409R FIG.30E of US 133 2016/0355600 Fc Heterodimerization T366I, K392M, F405A,Y407V FIG. 30E of US 134 T394W 2016/0355600 Fc Heterodimerization T366V,K409F L351Y, Y407A FIG. 30E of US 135 2016/0355600 Fc HeterodimerizationT366A, K392E, D399R, S400R, FIG. 30E of US 136 K409F, T411E Y407A2016/0355600 Fc Heterodimerization L351K L351E FIG. 30E of US 1372016/0355600 Fc Heterodimerization H99T, N203D, Q196K, L199T, FIG. 30Eof US 138 K247Q,R355Q, P217R, P228R, 2016/0355600 Q419E, K447 N276K FcHeterodimerization I199T, N203D, Q196K, I199T, FIG. 30E of US 139K247Q,R355Q, N276K 2016/0355600 Q419E, K447 Fc Heterodimerization I199T,N203D, FIG. 30E of US 140 K274Q, R355Q, 2016/0355600 N384S, K392N,V397M, Q419E DEL447 Fc Heterodimerization N208D, Q295E FIG. 30E of US141 N384D, Q418E 2016/0355600 N421D Fc Heterodimerization N208D, Q295EFIG. 30E of US 142 Q418E, N421D 2016/0355600 Fc HeterodimerizationQ196K, I199T FIG. 30E of US 143 P217R, P228R 2016/0355600 N276K FcHeterodimerization Q196K, I199T FIG. 30E of US 144 N276K 2016/0355600 FcHeterodimerization E269Q, E272Q FIG. 30E of US 145 E283Q, E357Q2016/0355600 Fc Heterodimerization E269Q, E272Q FIG. 30E of US 146E283Q, 2016/0355600 Fc Heterodimerization E269Q, E272Q FIG. 30E of US147 2016/0355600 Fc Heterodimerization E269Q, E283Q FIG. 30E of US 1482016/0355600 Fc Heterodimerization E272Q, E283Q FIG. 30E of US 1492016/0355600 Fc Heterodimerization E269Q FIG. 30E of US 150 2016/0355600

Exemplary pairs of heterologous, non-identical Fc sequences that canpair to form a Fc heterodimer, and which can be included in MBM of thedisclosure, include (i) SEQ ID NO:869 and SEQ ID NO:870, and (ii) SEQ IDNO:869 and SEQ ID NO:871.

(SEQ ID NO: 869) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 870)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 871)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGKAn Fc region having an amino acid sequence of one of SEQ ID NOS: 869-871can be modified to include one or more of the substitutions described inSection 7.3.1 (including its subparts), for example to include thesubstitution(s) corresponding to an ablation variant set forth in Table3. In some embodiments, a MBM comprises an Fc region having an aminoacid sequence of one of SEQ ID NOs:869-871 with a mutation at 1, 2, 3,4, 5, 6, or more than 6 of positions 233, 234, 235, 236, 237, 239, 265,266, 267, 268, 269, 297, 299, 322, 327, 328, 329, 330, 331 and 332 (EUnumbering), for example mutation(s) described in Section 7.3.1(including its subparts). For example, a MBM can comprise an Fc regionhaving an amino acid sequence of SEQ ID NO:869 with a mutation at 1, 2,3, 4, 5, 6, or more than 6 of positions 233, 234, 235, 236, 237, 239,265, 266, 267, 268, 269, 297, 299, 322, 327, 328, 329, 330, 331 and 332and/or an Fc region having an amino acid sequence of SEQ ID NO:870 witha mutation at 1, 2, 3, 4, 5, 6, or more than 6 of positions 233, 234,235, 236, 237, 239, 265, 266, 267, 268, 269, 297, 299, 322, 327, 328,329, 330, 331 and 332 and/or an Fc region having an amino acid sequenceof SEQ ID NO:871 with a mutation at 1, 2, 3, 4, 5, 6, or more than 6 ofpositions 233, 234, 235, 236, 237, 239, 265, 266, 267, 268, 269, 297,299, 322, 327, 328, 329, 330, 331 and 332.

7.3.1.5.1. Steric Variants

MBMs (e.g., TBMs) can comprise one or more, e.g., a plurality, ofmodifications to one or more of the constant domains of an Fc domain,e.g., to the CH3 domains. In one example, a MBM (e.g., a TBM) comprisestwo polypeptides that each comprise a heavy chain constant domain of anantibody, e.g., a CH2 or CH3 domain. In an example, the two heavy chainconstant domains, e.g., the CH2 or CH3 domains of the MBM (e.g., TBM)comprise one or more modifications that allow for a heterodimericassociation between the two chains. In one aspect, the one or moremodifications are disposed on CH2 domains of the two heavy chains. Inone aspect, the one or more modifications are disposed on CH3 domains ofat least two polypeptides of the MBM.

One mechanism for Fc heterodimerization is generally referred to in theart as “knobs and holes”, or “knob-in-holes”, or “knobs-into-holes”.These terms refer to amino acid mutations that create steric influencesto favor formation of Fc heterodimers over Fc homodimers, as describedin, e.g., Ridgway et al., 1996, Protein Engineering 9(7):617; Atwell etal., 1997, J. Mol. Biol. 270:26; U.S. Pat. No. 8,216,805. Knob-in-holemutations can be combined with other strategies to improveheterodimerization.

In one aspect, the one or more modifications to a first polypeptide ofthe MBM comprising a heavy chain constant domain can create a “knob” andthe one or more modifications to a second polypeptide of the MBM createsa “hole,” such that heterodimerization of the polypeptide of the MBMcomprising a heavy chain constant domain causes the “knob” to interface(e.g., interact, e.g., a CH2 domain of a first polypeptide interactingwith a CH2 domain of a second polypeptide, or a CH3 domain of a firstpolypeptide interacting with a CH3 domain of a second polypeptide) withthe “hole.” The “knob” projects from the interface of a firstpolypeptide of the MBM comprising a heavy chain constant domain and istherefore positionable in a compensatory “hole” in the interface with asecond polypeptide of the MBM comprising a heavy chain constant domainso as to stabilize the heteromultimer, and thereby favor heteromultimerformation over homomultimer formation, for example. The knob can ex istin the original interface or can be introduced synthetically (e.g. byaltering nucleic acid encoding the interface). The import residues forthe formation of a knob are generally naturally occurring amino acidresidues and can be selected from arginine (R), phenylalanine (F),tyrosine (Y) and tryptophan (W). In some cases, tryptophan and tyrosineare selected. In an embodiment, the original residue for the formationof the protuberance has a small side chain volume, such as alanine,asparagine, aspartic acid, glycine, serine, threonine or valine.

A “hole” comprises at least one amino acid side chain which is recessedfrom the interface of a second polypeptide of the MBM comprising a heavychain constant domain and therefore accommodates a corresponding knob onthe adjacent interfacing surface of a first polypeptide of the MBMcomprising a heavy chain constant domain. The hole can ex ist in theoriginal interface or can be introduced synthetically (e.g. by alteringnucleic acid encoding the interface). The import residues for theformation of a hole are usually naturally occurring amino acid residuesand are in some embodiments selected from alanine (A), serine (S),threonine (T) and valine (V). In one embodiment, the amino acid residueis serine, alanine or threonine. In another embodiment, the originalresidue for the formation of the hole has a large side chain volume,such as tyrosine, arginine, phenylalanine or tryptophan.

In an embodiment, a first CH3 domain is modified at residue 366, 405 or407 to create either a “knob” or a hole” (as described above), and thesecond CH3 domain that heterodimerizes with the first CH3 domain ismodified at: residue 407 if residue 366 is modified in the first CH3domain, residue 394 if residue 405 is modified in the first CH3 domain,or residue 366 if residue 407 is modified in the first CH3 domain tocreate a “hole” or “knob” complementary to the “knob” or “hole” of thefirst CH3 domain.

In another embodiment, a first CH3 domain is modified at residue 366,and the second CH3 domain that heterodimerizes with the first CH3 domainis modified at residues 366, 368 and/or 407, to create a “hole” or“knob” complementary to the “knob” or “hole” of the first CH3 domain. Inone embodiment, the modification to the first CH3 domain introduces atyrosine (Y) residue at position 366. In an embodiment, the modificationto the first CH3 is T366Y. In one embodiment, the modification to thefirst CH3 domain introduces a tryptophan (W) residue at position 366. Inan embodiment, the modification to the first CH3 is T366W. In someembodiments, the modification to the second CH3 domain thatheterodimerizes with the first CH3 domain modified at position 366(e.g., has a tyrosine (Y) or tryptophan (W) introduced at position 366,e.g., comprises the modification T366Y or T366W), comprises amodification at position 366, a modification at position 368 and amodification at position 407. In some embodiments, the modification atposition 366 introduces a serine (S) residue, the modification atposition 368 introduces an alanine (A), and the modification at position407 introduces a valine (V). In some embodiments, the modificationscomprise T366S, L368A and Y407V. In one embodiment, the first CH3 domainof the multispecific molecule comprises the modification T366Y, and thesecond CH3 domain that heterodimerizes with the first CH3 domaincomprises the modifications T366S, L368A and Y407V, or vice versa. Inone embodiment, the first CH3 domain of the multispecific moleculecomprises the modification T366W, and the second CH3 domain thatheterodimerizes with the first CH3 domain comprises the modificationsT366S, L368A and Y407V, or vice versa.

Additional steric or “skew” (e.g., knob-in-hole) modifications aredescribed in PCT publication no. WO2014/145806 (for example, FIG. 3 ,FIG. 4 and FIG. 12 of WO2014/145806), PCT publication no. WO2014/110601,and PCT publication no. WO 2016/086186, WO 2016/086189, WO 2016/086196and WO 2016/182751. An example of a KIH variant comprises a firstconstant chain comprising a L368D and a K370S modification, paired witha second constant chain comprising a S364K and E357Q modification.

Additional knob-in-hole modification pairs suitable for use in any ofthe MBMs of the present disclosure are further described in, forexample, WO1996/027011, and Merchant et al., 1998, Nat. Biotechnol.,16:677-681.

In further embodiments, the CH3 domains can be additionally modified tointroduce a pair of cysteine residues. Without being bound by theory, itis believed that the introduction of a pair of cysteine residues capableof forming a disulfide bond provide stability to heterodimerized MBMs(e.g., TBMs) comprising paired CH3 domains. In some embodiments, thefirst CH3 domain comprises a cysteine at position 354, and the secondCH3 domain that heterodimerizes with the first CH3 domain comprises acysteine at position 349. In some embodiments, the first CH3 domaincomprises a cysteine at position 354 (e.g., comprises the modificationS354C) and a tyrosine (Y) at position 366 (e.g., comprises themodification T366Y), and the second CH3 domain that heterodimerizes withthe first CH3 domain comprises a cysteine at position 349 (e.g.,comprises the modification Y349C), a serine at position 366 (e.g.,comprises the modification T366S), an alanine at position 368 (e.g.,comprises the modification L368A), and a valine at position 407 (e.g.,comprises the modification Y407V). In some embodiments, the first CH3domain comprises a cysteine at position 354 (e.g., comprises themodification S354C) and a tryptophan (VV) at position 366 (e.g.,comprises the modification T366W), and the second CH3 domain thatheterodimerizes with the first CH3 domain comprises a cysteine atposition 349 (e.g., comprises the modification Y349C), a serine atposition 366 (e.g., comprises the modification T366S), an alanine atposition 368 (e.g., comprises the modification L368A), and a valine atposition 407 (e.g., comprises the modification Y407V).

An additional mechanism that finds use in the generation of heterodimersis sometimes referred to as “electrostatic steering” as described inGunasekaran et al., 2010, J. Biol. Chem. 285(25):19637. This issometimes referred to herein as “charge pairs”. In this embodiment,electrostatics are used to skew the formation towardsheterodimerization. These can also have an effect on pl, and thus onpurification, and thus could in some cases also be considered plvariants. However, as these were generated to force heterodimerizationand were not used as purification tools, they are classified as “stericvariants”. These include, but are not limited to, D221E/P228E/L368Epaired with D221R/P228R/K409R and C220E/P228E, 368E paired withC220R/E224R/P228R/K409R.

Additional variants that can be combined with other variants, optionallyand independently in any amount, such as pI variants outlined herein orother steric variants that are shown in FIG. 37 of US 2012/0149876.

In some embodiments, the steric variants outlined herein can beoptionally and independently incorporated with any pI variant (or othervariants such as Fc variants, FcRn variants) into one or both Fcregions, and can be independently and optionally included or excludedfrom the MBMs of the disclosure.

A list of suitable skew variants is found in Table 4 showing some pairsof particular utility in many embodiments. Of particular use in manyembodiments are the pairs of sets including, but not limited to,S364K/E357Q : L368D/K370S; L368D/K370S : S364K; L368E/K370S : S364K;T411T/E360E/Q362E : D401K; L368D/K370S : S364K/E357L; and K370S :S364K/E357Q. In terms of nomenclature, the pair “S364K/E357Q :L368D/K370S” means that one of the Fc regions has the double variant setS364K/E357Q and the other has the double variant set L368D/K370S.

TABLE 4 Exemplary skew variants Fc region 1 Fc region 2 F405A T394FS364D Y349K S364E L368K S364E Y349K S364F K370G S364H Y349K S364H Y349TS364Y K370G T411K K370E V397S/F405A T394F K370R/T411K K370E/T411EL351E/S364D Y349K/L351K L351E/S364E Y349K/L351K L351E/T366D L351K/T366KP395T/V397S/F405A T394F S364D/K370G S364Y/K370R S364D/T394F Y349K/F405AS364E/F405A Y349K/T394F S364E/F405S Y349K/T394Y S364E/T411E Y349K/D401KS364H/D401K Y349T/T411E S364H/F405A Y349T/T394F S364H/T394F Y349T/F405AY349C/S364E Y349K/S354C L351E/S364D/F405A Y349K/L351K/T394FL351K/S364H/D401K Y349T/L351E/T411E S364E/T411E/F405A Y349K/T394F/D401KS364H/D401K/F405A Y349T/T394F/T411E S364H/F405A/T411E Y349T/T394F/D401KK370E/T411D T411K L368E/K409E L368K Y349T/T394F/S354C S364H/F405A/Y349CT411E D401K T411E D401R/T411R Q347E/K360E Q347R L368E S364K L368E/K370SS364K L368E/K370T S364K L368E/D401R S364K L368E/D401N S364K L368EE357S/S364K L368E S364K/K409E L368E S364K/K409V L368D S364K L368D/K370SS364K L368D/K370S S364K/E357L L368D/K370S S364K/E357Q T411E/K360E/Q362ED401K K370S S364K L368E/K370S S364K/E357Q K370S S364K/E357Q T411E/K360DD401K T411E/K360E D401K T411E/Q362E D401K T411E/N390D D401K T411ED401K/Q347K T411E D401K/Q347R T411E/K360D/Q362E D401K K392D/K409DE356K/D399K K370D/K392D/K409D E356K/E357K/D399KI199T/N203D/K247Q/R355Q/N384S/ Q196K/I199T/P217R/K392N/V397M/Q419E/K447_ P228R/N276K I199T/N203D/K247Q/R355Q/N384S/Q196K/I199T/N276K K392N/V397M/Q419E/K447_ N384S/K392N/V397M/Q419E N276KD221E/P228E/L368E D221R/P228R/K409R C220E/P228E/L368E C220R/E224R/P228R/K409R F405L K409R T366I/K392M/T394W F405A/Y407V T366V/K409F L351Y/Y407AT366A/K392E/K409F/T411E D399R/S400R/Y407A L351K L351EI199T/N203D/K247Q/R355Q/Q419E/K447_ Q196K/I199T/P217R/ P228R/N276KI199T/N203D/K247Q/R355Q/Q419E/K447_ Q196K/I199T/N276K I199T N203D K274QR355Q N384S K392N V397M Q419E DEL447 N208D Q295E N384D Q418E N421D N208DQ295E Q418E N421D Q196K I199T P217R P228R N276K Q196K I199T N276K E269QE272Q E283Q E357Q E269Q E272Q E283Q E269Q E272Q E269Q E283Q E272Q E283QE269Q T411E/K360E/N390D D401K T411E/Q362E/N390D D401K T411E/Q347RD401K/K360D T411E/Q347R D401K/K360E T411E/K360 D401K/Q347K T411E/K360DD401K/Q347R T411E/K360E D401K/Q347K T411E/K360E D401K/Q347R T411E/S364KD401K/K370S T411E/K370S D401K/S364K Q347E E357Q Q347E E357Q/Q362KK360D/Q362E Q347R K360D/Q362E D401K K360D/Q362E Q347R/D401K K360E/Q362EQ347R K360E/Q362E D401K K360E/Q362E Q347R/D401K Q362E/N390D D401KQ347E/K360D D401N K360D Q347R/N390K K360D N390K/D401N K360E Y349HK370S/Q347E S364K K370S/E357L S364K K370S/E357Q S364K K370S/Q347E/E357LS364K K370S/Q347E/E357Q S364K L368D/K370S/Q347E S364K L368D/K370S/E357LS364K L368D/K370S/E357Q S364K L368D/K370S/Q347E/E357L S364KL368D/K370S/Q347E/E357Q S364K L368E/K370S/Q347E S364K L368E/K370S/E357LS364K L368E/K370S/E357Q S364K L368E/K370S/Q347E/E357L S364KL368E/K370S/Q347E/E357Q S364K L368D/K370T/Q347E S364K L368D/K370T/E357LS364K L368D/K370T/E357Q S364K L368D/K370T/Q347E/E357L S364KL368D/K370T/Q347E/E357Q S364K L368E/K370T/Q347E S364K L368E/K370T/E357LS364K L368E/K370T/E357Q S364K L368E/K370T/Q347E/E357L S364KL368E/K370T/Q347E/E357Q S364K T411E/Q362E D401K/T411K T411E/N390DD401K/T411K T411E/Q362E D401R/T411R T411E/N390D D401R/T411R Y407T T366YF405A T394W T366Y/F405A T394W/Y407T Y407A T366W T366S/L368A/Y407V T366WT366S/L368A/Y407V/Y349C T366W/S354C K392D/K409D E356K/D399KK370D/K392D/K409D E356K/E357K/D399K I199T/N203D/K247Q/R355Q/N384S/Q196K/I199T/P217R/ K392N/V397M/Q419E/K447_ P228R/N276KI199T/N203D/K247Q/R355Q/N384S/ Q196K/I199T/N276K K392N/V397M/Q419E/K447_N384S/K392N/V397M/Q419E N276K D221E/P228E/L368E D221R/P228R/K409RC220E/P228E/L368E C220R/E224R/P228R/ K409R F405L K409R T366I/K392M/T394WF405A/Y407V T366V/K409F L351Y/Y407A T366A/K392E/K409F/T411ED399R/S400R/Y407A L351K L351E I199T/N203D/K247Q/R355Q/Q419E/K447_Q196K/I199T/P217R/ P228R/N276K I199T/N203D/K247Q/R355Q/Q419E/K447_Q196K/I199T/N276K I199T N203D K274Q R355Q N384S K392N V397M Q419E DEL447N208D Q295E N384D Q418E N421D Q295E N384D Q418E N421D N208D Q295E Q418EN421D Q295EQ418E N421D Q196K I199T P217R P228R N276K Q196K I199T N276KE269Q E272Q E283Q E357Q E269Q E272Q E283Q E269Q E272Q E269Q E283Q E272QE283Q E269Q

In some embodiments, a MBM comprises a first Fc region and a second Fcregion. In some embodiments, the first Fc region comprises the followingmutations: L368D and K370S, and the second Fc region comprises thefollowing mutations: S364K and E357Q. In some embodiments, the first Fcregion comprises the following mutations: S364K and E357Q, and thesecond Fc region comprises the following mutations: L368D and K370S.

7.3.1.5.2. Alternative Knob and Hole: IgG Heterodimerization

Heterodimerization of polypeptide chains of a MBM (e.g., a TBM)comprising paired CH3 domains can be increased by introducing one ormore modifications in a CH3 domain which is derived from the IgG1antibody class. In an embodiment, the modifications comprise a K409Rmodification to one CH3 domain paired with F405L modification in thesecond CH3 domain. Additional modifications can also, or alternatively,be at positions 366, 368, 370, 399, 405, 407, and 409. In some cases,heterodimerization of polypeptides comprising such modifications isachieved under reducing conditions, e.g., 10-100 mM 2-MEA (e.g., 25, 50,or 100 mM 2-MEA) for 1-10, e.g., 1.5-5, e.g., 5, hours at 25-37C, e.g.,25C or 37C.

The amino acid replacements described herein can be introduced into theCH3 domains using techniques which are well known (see, e.g., McPherson,ed., 1991, Directed Mutagenesis: a Practical Approach; Adelman et al.,1983, DNA, 2:183).

The IgG heterodimerization strategy is further described in, forexample, WO2008/119353, WO2011/131746, and WO2013/060867.

In any of the embodiments described in this Section, the CH3 domains canbe additionally modified to introduce a pair of cysteine residues asdescribed in Section 7.3.1.3.

7.3.1.5.3. pI (Isoelectric Point) Variants

In general, as a skilled artisan will appreciate, there are two generalcategories of pl variants: those that increase the pI of the protein(basic changes) and those that decrease the pl of the protein (acidicchanges). As described herein, all combinations of these variants can bedone: one Fc region can be wild type, or a variant that does not displaya significantly different pI from wild-type, and the other can be eithermore basic or more acidic. Alternatively, each Fc region is changed, oneto more basic and one to more acidic.

Exemplary combinations of pI variants are shown in Table 5. As outlinedherein and shown in Table 5, these changes are shown relative to IgG1,but all isotypes can be altered this way, as well as isotype hybrids. Inthe case where the heavy chain constant domain is from IgG2-4, R133E andR133Q can also be used.

TABLE 5 Exemplary pl Variant Combinations Variant constant regionSubstitutions pl_ISO(−) I199T N203D K274Q R355Q N384S K392N V397M Q419EDEL447 pl_(−)_isosteric_A N208D Q295E N384D Q418E N421D pl_(−)_isostericA-Fc only Q295E N384D Q418E N421D pl_(−)_isosteric_B N208D Q295E Q418EN421D pl_(−)_isosteric_B-Fc only Q295E Q418E N421D pl_ISO(+RR) Q196KI199T P217R P228R N276K pl_ISO(+) Q196K I199T N276K pl_(+)_isosteric_AE269Q E272Q E283Q E357Q pl_(+)_isosteric_B E269Q E272Q E283Qpl_(+)_isosteric_E269Q/E272Q E269Q E272Q pl_(+)_isosteric_E269Q/E283QE269Q E283Q pl_(+)_isosteric_E272Q/E283Q E272Q E283Qpl_(+)_isosteric_E269Q E269Q

In one embodiment, a combination of pI variants has one Fc region (thenegative Fab side) comprising 208D, 295E, 384D, 418E, 421D variants(N208D/Q295E/N384D/Q418E/N421D when relative to human IgG1) and a secondFc region (the positive scFv side) comprising a positively charged scFvlinker, e.g., L36 (described in Section 7.3.3). However, as a skilledartisan will appreciate, the first Fc region includes a CH1 domain,including position 208. Accordingly, in constructs that do not include aCH1 domain (for example for MBMs that do not utilize a CH1 domain as oneof the domains, for example in a format depicted in FIG. 1K), a negativepI variant Fc set can include 295E, 384D, 418E, 421D variants(Q295E/N384D/Q418E/N421D when relative to human IgG1).

In some embodiments, a first Fc region has a set of substitutions fromTable 5 and a second Fc region is connected to a charged linker (e.g.,selected from those described in Section 7.3.3).

In some embodiments, a MBM comprises a first Fc region and a second Fcregion. In some embodiments, the first Fc region comprises the followingmutations: N208D, Q295E, N384D, Q418E, and N421D. In some embodiments,the second Fc region comprises the following mutations: N208D, Q295E,N384D, Q418E, and N421D.

7.3.1.5.4. Isotopic Variants

In addition, many embodiments of the disclosure rely on the“importation” of pI amino acids at particular positions from one IgGisotype into another, thus reducing or eliminating the possibility ofunwanted immunogenicity being introduced into the variants. A number ofthese are shown in FIG. 21 of US Publ. 2014/0370013. That is, IgG1 is acommon isotype for therapeutic antibodies for a variety of reasons,including high effector function. However, the heavy constant region ofIgG1 has a higher pI than that of IgG2 (8.10 versus 7.31). Byintroducing IgG2 residues at particular positions into the IgG1backbone, the pI of the resulting Fc region is lowered (or increased)and additionally exhibits longer serum half-life. For example, IgG1 hasa glycine (pI 5.97) at position 137, and IgG2 has a glutamic acid (pI3.22); importing the glutamic acid will affect the pI of the resultingprotein. As is described below, a number of amino acid substitutions aregenerally required to significantly affect the pI of the variantantibody. However, it should be noted as discussed below that evenchanges in IgG2 molecules allow for increased serum half-life.

In other embodiments, non-isotypic amino acid changes are made, eitherto reduce the overall charge state of the resulting protein (e.g., bychanging a higher pI amino acid to a lower pl amino acid), or to allowaccommodations in structure for stability, as is further describedbelow.

In addition, by pI engineering both the heavy and light constant domainsof a MBM comprising two half antibodies, significant changes in eachhalf antibody can be seen. Having the pls of the two half antibodiesdiffer by at least 0.5 can allow separation by ion exchangechromatography or isoelectric focusing, or other methods sensitive toisoelectric point.

7.3.1.5.5. Calculating pI

The pI of a half antibody comprising an Fc region and a ABD or ABD chaincan depend on the pI of the variant heavy chain constant domain and thepI of the total half antibody, including the variant heavy chainconstant domain and ABD or ABD chain. Thus, in some embodiments, thechange in pI is calculated on the basis of the variant heavy chainconstant domain, using the chart in the FIG. 19 of US Pub. 2014/0370013.As discussed herein, which half antibody to engineer is generallydecided by the inherent pI of the half antibodies. Alternatively, the pIof each half antibody can be compared.

7.3.1.5.6. pI Variants that also Confer Better FcRn In Vivo Binding

In the case where a pI variant decreases the pI of an Fc region, it canhave the added benefit of improving serum retention in vivo.

pI variant Fc regions are believed to provide longer half-lives toantigen binding molecules in vivo, because binding to FcRn at pH 6 in anendosome sequesters the Fc (Ghetie and Ward, 1997, Immunol Today.18(12): 592-598). The endosomal compartment then recycles the Fc to thecell surface. Once the compartment opens to the extracellular space, thehigher pH ˜7.4, induces the release of Fc back into the blood. In mice,DaII' Acqua et al. showed that Fc mutants with increased FcRn binding atpH 6 and pH 7.4 actually had reduced serum concentrations and the samehalf life as wild-type Fc (DaIl' Acqua et al,. 2002, J. Immunol.169:5171-5180). The increased affinity of Fc for FcRn at pH 7.4 isthought to forbid the release of the Fc back into the blood. Therefore,the Fc mutations that will increase Fc's half-life in vivo will ideallyincrease FcRn binding at the lower pH while still allowing release of Fcat higher pH. The amino acid histidine changes its charge state in thepH range of 6.0 to 7.4. Therefore, it is not surprising to find Hisresidues at important positions in the Fc/FcRn complex.

It has been suggested that antibodies with variable regions that havelower isoelectric points can also have longer serum half-lives (Igawa etal., 2010, PEDS. 23(5): 385-392). However, the mechanism of this isstill poorly understood. Moreover, variable regions differ from antibodyto antibody. Constant region variants with reduced pl and extendedhalf-life would provide a more modular approach to improving thepharmacokinetic properties of MBMs, as described herein.

7.3.1.5.7. Polar Bridge

Heterodimerization of polypeptide chains of MBMs (e.g., TBMs) comprisingan Fc domain can be increased by introducing modifications based on the“polar-bridging” rationale, which is to make residues at the bindinginterface of the two polypeptide chains to interact with residues ofsimilar (or complimentary) physical property in the heterodimerconfiguration, while with residues of different physical property in thehomodimer configuration. In particular, these modifications are designedso that, in the heterodimer formation, polar residues interact withpolar residues, while hydrophobic residues interact with hydrophobicresidues. In contrast, in the homodimer formation, residues are modifiedso that polar residues interact with hydrophobic residues. The favorableinteractions in the heterodimer configuration and the unfavorableinteractions in the homodimer configuration work together to make itmore likely for Fc regions to form heterodimers than to form homodimers.

In an exemplary embodiment, the above modifications are generated at oneor more positions of residues 364, 368, 399, 405, 409, and 411 of a CH3domain.

In some embodiments, one or more modifications selected from the groupconsisting of S364L, T366V, L368Q, N399K, F405S, K409F and R411K areintroduced into one of the two CH3 domains. One or more modificationsselected from the group consisting of Y407F, K409Q and T411N can beintroduced into the second CH3 domain.

In another embodiment, one or more modifications selected from the groupconsisting of S364L, T366V, L368Q, D399K, F405S, K409F and T411K areintroduced into one CH3 domain, while one or more modifications selectedfrom the group consisting of Y407F, K409Q and T411D are introduced intothe second CH3 domain.

In one exemplary embodiment, the original residue of threonine atposition 366 of one CH3 domain is replaced by valine, while the originalresidue of tyrosine at position 407 of the other CH3 domain is replacedby phenylalanine.

In another exemplary embodiment, the original residue of serine atposition 364 of one CH3 domain is replaced by leucine, while theoriginal residue of leucine at position 368 of the same CH3 domain isreplaced by glutamine.

In yet another exemplary embodiment, the original residue ofphenylalanine at position 405 of one CH3 domain is replaced by serineand the original residue of lysine at position 409 of this CH3 domain isreplaced by phenylalanine, while the original residue of lysine atposition 409 of the other CH3 domain is replaced by glutamine.

In yet another exemplary embodiment, the original residue of asparticacid at position 399 of one CH3 domain is replaced by lysine, and theoriginal residue of threonine at position 411 of the same CH3 domain isreplaced by lysine, while the original residue of threonine at position411 of the other CH3 domain is replaced by aspartic acid.

The amino acid replacements described herein can be introduced into theCH3 domains using techniques which are well known (see, e.g., McPherson,ed., 1991, Directed Mutagenesis: a Practical Approach; Adelman et al.,1983, DNA, 2:183). The polar bridge strategy is described in, forexample, WO2006/106905, WO2009/089004 and K. Gunasekaran, et al. (2010)JBC, 285:19637-19646.

Additional polar bridge modifications are described in, for example, PCTpublication no. WO2014/145806 (for example, FIG. 6 of WO2014/145806),PCT publication no. WO2014/110601, and PCT publication no. WO2016/086186, WO 2016/086189, WO 2016/086196 and WO 2016/182751. Anexample of a polar bridge variant comprises a constant chain comprisinga N208D, Q295E, N384D, Q418E and N421D modification.

In any of the embodiments described herein, the CH3 domains can beadditionally modified to introduce a pair of cysteine residues asdescribed in Section 7.3.1.3.

Additional strategies for enhancing heterodimerization are described in,for example, WO2016/105450, WO2016/086186, WO2016/086189, WO2016/086196,WO2016/141378, and WO2014/145806, and WO2014/110601. Any of thestrategies can be employed in a MBM described herein.

7.3.1.6. Combination of Heterodimerization Variants and Other FcVariants

As will be appreciated by a skilled artisan, all of the recitedheterodimerization variants (including skew and/or pI variants) can beoptionally and independently combined in any way, as long as the Fcregions of an Fc domain retain their ability to dimerize. In addition,all of these variants can be combined into any of the heterodimerizationformats.

In the case of pI variants, while embodiments finding particular use areshown in the Table 5, other combinations can be generated, following thebasic rule of altering the pl difference between two Fc regions in an Fcheterodimer to facilitate purification.

In addition, any of the heterodimerization variants, skew and pl, arealso independently and optionally combined with Fc ablation variants, Fcvariants, FcRn variants, as generally outlined herein.

In some embodiments, a particular combination of skew and pI variantsthat finds use in the present disclosure is T366S/L368A/Y407V:T366W(optionally including a bridging disulfide,T366S/L368A/Y407V/Y349C:T366W/S354C) with one Fc region comprisingQ295E/N384D/Q418E/N481D and the other a positively charged scFv linker(when the format includes an scFv domain). As will be appreciated by askilled artisan, the “knobs in holes” variants do not change pl, andthus can be used on either one of the Fc regions in an Fc heterodimer.

In some embodiments, first and second Fc regions that find use thepresent disclosure include the amino acid substitutionsS364K/E357Q:L368D/K370S, where the first and/or second Fc regionincludes the ablation variant substitutions233P/L234V/L235A/G236del/S267K, and the first and/or second Fc regioncomprises the pl variant substitutions N208D/Q295E/N384D/Q418E/N421D(pl_(−)_isosteric_A).

7.3.2. Hinge Regions

The MBMs (e.g., TBMs) can also comprise hinge regions, e.g., connectingan antigen-binding module to an Fc region. The hinge region can be anative or a modified hinge region. Hinge regions are typically found atthe N-termini of Fc regions.

A native hinge region is the hinge region that would normally be foundbetween Fab and Fc domains in a naturally occurring antibody. A modifiedhinge region is any hinge that differs in length and/or composition fromthe native hinge region. Such hinges can include hinge regions fromother species, such as human, mouse, rat, rabbit, shark, pig, hamster,camel, llama or goat hinge regions. Other modified hinge regions cancomprise a complete hinge region derived from an antibody of a differentclass or subclass from that of the heavy chain Fc region. Alternatively,the modified hinge region can comprise part of a natural hinge or arepeating unit in which each unit in the repeat is derived from anatural hinge region. In a further alternative, the natural hinge regioncan be altered by converting one or more cysteine or other residues intoneutral residues, such as serine or alanine, or by converting suitablyplaced residues into cysteine residues. By such means the number ofcysteine residues in the hinge region can be increased or decreased.This approach is described further in U.S. Pat. No. 5,677,425 by Bodmeret al.. Altering the number of cysteine residues in a hinge region can,for example, facilitate assembly of light and heavy chains, or increaseor decrease the stability of a MBM. Other modified hinge regions can beentirely synthetic and can be designed to possess desired propertiessuch as length, cysteine composition and flexibility.

A number of modified hinge regions have been described for example, inU.S. Pat. No. 5,677,425, WO9915549, WO2005003170, WO2005003169,WO2005003170, WO9825971 and WO2005003171.

Examples of suitable hinge sequences are shown in Table 6.

TABLE 6 Hinge Sequences Hinge Hinge SEQ ID Name DescriptionHinge Sequence NO: H1 Human IgA1 VPSTPPTPSPSTPPTPSPS  4 H2 Human IgA2VPPPPP  5 H3 Human IgD ESPKAQASSVPTAQPQAEGSLAKATTAPATTRN  6TGRGGEEKKKEKEKEEQEERETKTP H4 Human IgG1 EPKSCDKTHTCPPCP  7 H5 Human IgG2ERKCCVECPPCP  8 H6 Human IgG3 ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPE  9PKSCDTPPPCPRCPEPKSCDTPPPCPRCP H7 Human IgG4 ESKYGPPCPSCP 10 H8Human IgG4(P) ESKYGPPCPPCP 11 H9 Engineered v1 CPPC  2 H10 Engineered v2CPSC 12 H11 Engineered v3 CPRC 13 H12 Engineered v4 SPPC 14 H13Engineered v5 CPPS 15 H14 Engineered v6 SPPS  3 H15 Engineered v7DKTHTCAA 16 H16 Engineered v8 DKTHTCPPCPA 17 H17 Engineered v9DKTHTCPPCPATCPPCPA 18 H18 Engineered v10 DKTHTCPPCPATCPPCPATCPPCPA 19H19 Engineered v11 DKTHTCPPCPAGKPTLYNSLVMSDTAGTCY 20 H20 Engineered v12DKTHTCPPCPAGKPTHVNVSVVMAEVDGTCY 21 H21 Engineered v13 DKTHTCCVECPPCPA 22H22 Engineered v14 DKTHTCPRCPEPKSCDTPPPCPRCPA 23 H23 Engineered v15DKTHTCPSCPA 24

In one embodiment, the heavy chain Fc region possesses an intact hingeregion at its N-terminus.

In one embodiment, the heavy chain Fc region and hinge region arederived from IgG4 and the hinge region comprises the modified sequenceCPPC (SEQ ID NO: 2). The core hinge region of human IgG4 contains thesequence CPSC (SEQ ID NO: 12) compared to IgG1 which contains thesequence CPPC (SEQ ID NO: 2). The serine residue present in the IgG4sequence leads to increased flexibility in this region, and therefore aproportion of molecules form disulfide bonds within the same proteinchain (an intrachain disulfide) rather than bridging to the other heavychain in the IgG molecule to form the interchain disulfide. (Angel etal., 1993, Mol Immunol 30(1):105-108). Changing the serine residue to aproline to give the same core sequence as IgG1 allows complete formationof inter-chain disulfides in the IgG4 hinge region, thus reducingheterogeneity in the purified product. This altered isotype is termedIgG4P.

7.3.3. ABM Linkers

In certain aspects, the present disclosure provides MBMs (e.g., TBMs)comprising at least three ABMs, where two or more components of an ABM(e.g., a VH and a VL of an scFv), two or more ABMs, or an ABM and anon-ABM domain (e.g., a dimerization domain such as an Fc region) areconnected to one another by a peptide linker. Such linkers are referredto herein an “ABM linkers”, as opposed to the ADC linkers used to attachdrugs to MBMs as described, for example, in Section 7.10.2.

A peptide linker can range from 2 amino acids to 60 or more amino acids,and in certain aspects a peptide linker ranges from 3 amino acids to 50amino acids, from 4 to 30 amino acids, from 5 to 25 amino acids, from 10to 25 amino acids or from 12 to 20 amino acids. In particularembodiments, a peptide linker is 2 amino acids, 3 amino acids, 4 aminoacid, 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 aminoacids, 14 amino acid, 15 amino acids, 16 amino acids, 17 amino acids, 18amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 aminoacids, 23 amino acids, 24 amino acid, 25 amino acids, 26 amino acids, 27amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 aminoacids, 32 amino acids, 33 amino acids, 34 amino acid, 35 amino acids, 36amino acids, 37 amino acids, 38 amino acids, 39 amino acids, 40 aminoacids, 41 amino acids, 42 amino acids, 43 amino acids, 44 amino acid, 45amino acids, 46 amino acids, 47 amino acids, 48 amino acids, 49 aminoacids, or 50 amino acids in length.

Charged and/or flexible linkers can be used.

Examples of flexible ABM linkers that can be used in the MBMs includethose disclosed by Chen et al., 2013, Adv Drug Deliv Rev.65(10):1357-1369 and Klein et al., 2014, Protein Engineering, Design &Selection 27(10):325-330. A particularly useful flexible linker is(GGGGS)n (also referred to as (G4S)n) (SEQ ID NO: 25). In someembodiments, n is any number between 1 and 10, i.e., 1, 2, 3, 4, 5, 6,7, 8, 9, and 10, or any range bounded by any two of the foregoingnumbers, e.g., 1 to 5, 2 to 5, 3 to 6, 2 to 4, 1 to 4, and so on and soforth.

Other examples of suitable ABM linkers for use in the MBMs of thepresent disclosure are shown in Table 7 below:

TABLE 7 ABM Linker Sequences Linker SEQ ID Name Linker Sequence NO: L1ADAAP 26 L2 ADAAPTVSIFP 27 L3 ADAAPTVSIFPP 28 L4 AKTTAP 29 L5AKTTAPSVYPLAP 30 L6 AKTTPKLEEGEFSEARV 31 L7 AKTTPKLGG 32 L8 AKTTPP 33 L9AKTTPPSVTPLAP 34 L10 ASTKGP 35 L11 ASTKGPSVFPLAP 36 L12ASTKGPSVFPLAPASTKGPSVFPLAP 37 L13 EGKSSGSGSESKST 38 L14 GEGESGEGESGEGES39 L15 GEGESGEGESGEGESGEGES 40 L16 GEGGSGEGGSGEGGS 41 L17GENKVEYAPALMALS 42 L18 GGEGSGGEGSGGEGS 43 L19 GGGESGGEGSGEGGS 44 L20GGGESGGGESGGGES 45 L21(GGGGS)_(n) (also referred to as (G4S)_(n)), where n can 46 be 1-10. L22GGGGSGGGGS 47 L23 GGGGSGGGGSGGGGS  1 L24 GGGGSGGGGSGGGGSGGGGS 48 L25GGGKSGGGKSGGGKS 49 L26 GGGKSGGKGSGKGGS 50 L27 GGKGSGGKGSGGKGS 51 L28GGSGG 52 L29 GGSGGGGSG 53 L30 GGSGGGGSGGGGS 54 L31 GHEAAAVMQVQYPAS 55L32 GKGGSGKGGSGKGGS 56 L33 GKGKSGKGKSGKGKS 57 L34 GKGKSGKGKSGKGKSGKGKS58 L35 GKPGSGKPGSGKPGS 59 L36 GKPGSGKPGSGKPGSGKPGS 60 L37GPAKELTPLKEAKVS 61 L38 GSAGSAAGSGEF 62 L39 IRPRAIGGSKPRVA 63 L40KESGSVSSEQLAQFRSLD 64 L41 KTTPKLEEGEFSEAR 65 L42 QPKAAP 66 L43QPKAAPSVTLFPP 67 L44 RADAAAA(G4S)₄ 68 L45 RADAAAAGGPGS 69 L46 RADAAP 70L47 RADAAPTVS 71 L48 SAKTTP 72 L49 SAKTTPKLEEGEFSEARV 73 L50 SAKTTPKLGG74 L51 STAGDTHLGGEDFD 75 L52 TVAAP 76 L53 TVAAPSVFIFPP 77 L54TVAAPSVFIFPPTVAAPSVFIFPP 78

In various aspects, the disclosure provides a MBM (e.g., a TBM) whichcomprises one or more ABM linkers. Each of the ABM linkers can be rangefrom 2 amino acids to 60 amino acids in length, e.g., 4 to 30 aminoacids, from 5 to 25 amino acids, from 10 to 25 amino acids or from 12 to20 amino acids in length, optionally selected from Table 7 above. Inparticular embodiments, the MBM comprises two, three, four, five or sixABM linkers. The ABM linkers can be on one, two, three, four or evenmore polypeptide chains of the MBM.

7.4. Exemplary Trispecific Binding Molecules

Exemplary TBM configurations are shown in FIG. 1 . FIG. 1A shows thecomponents of the TBM configurations shown in FIGS. 1B-1V. The scFv,Fab, non-immunoglobulin based ABM, and Fc each can have thecharacteristics described for these components in Sections 7.2 and 7.3.The components of the TBM configurations shown in FIG. 1 can beassociated with each other by any of the means described in Sections 7.2and 7.3 (e.g., by direct bonds, ABM linkers, disulfide bonds, Fc domainswith modified with knob-in-hole interactions, etc.). The orientationsand associations of the various components shown in FIG. 1 are merelyexemplary; as will be appreciated by a skilled artisan, otherorientations and associations can be suitable (e.g., as described inSections 7.2 and 7.3).

TBMs are not limited to the configurations shown in FIG. 1 . Otherconfigurations that can be used are known to those skilled in the art.See, e.g., WO 2014/145806; WO 2017/124002; Liu et al., 2017, FrontImmunol. 8:38; Brinkmann & Kontermann, 2017, mAbs 9:2, 182-212; US2016/0355600; Klein et al., 2016, MAbs 8(6):1010-20; and US2017/0145116.

7.4.1. Exemplary Trivalent TBMs

The TBMs of the disclosure can be trivalent, i.e., they have threeantigen-binding domains, one of which binds BCMA, one of which binds acomponent of a TCR complex, and one of which binds either CD2 or a TAA.

Exemplary trivalent TBM configurations are shown in FIGS. 1B through 1P.

As depicted in FIGS. 1B-1K and 1N-1P, a TBM can comprise two halfantibodies, one comprising two ABMs and the other comprising one ABM,the two halves paired through an Fc domain.

In the embodiment of FIG. 1B, the first (or left) half antibodycomprises an scFv and an Fc region, and the second (or right) halfantibody comprises a Fab, an scFv and an Fc region. The first and secondhalf antibodies are associated through the Fc regions forming an Fcdomain.

In the embodiment of FIG. 1C, the first (or left) half antibodycomprises two Fab and an Fc region, and the second (or right) halfantibody comprises a Fab and an Fc region. The first and second halfantibodies are associated through the Fc regions forming an Fc domain.

In the embodiment of FIG. 1D, the first (or left) half antibodycomprises a Fab, an scFv and an Fc region, and the second (or right)half antibody comprises a Fab and an Fc region. The first and secondhalf antibodies are associated through the Fc regions forming an Fcdomain.

In the embodiment of FIG. 1E, the first (or left) half antibodycomprises an scFv and an Fc region, and the second (or right) halfantibody comprises two Fab and an Fc region. The first and second halfantibodies are associated through the Fc regions forming an Fc domain.

In the embodiment of FIG. 1F, the first (or left) half antibodycomprises an scFv, an Fc region, and a Fab, and the second (or right)half antibody comprises a Fab and an Fc region. The first and secondhalf antibodies are associated through the Fc regions forming an Fcdomain.

In the embodiment of FIG. 1G, the first (or left) half antibodycomprises an scFv and an Fc region, and the second (or right) halfantibody comprises a Fab an Fc region, and an scFV. The first and secondhalf antibodies are associated through the Fc regions forming an Fcdomain.

In the embodiment of FIG. 1H, the first (or left) half antibodycomprises two Fab and an Fc region, and the second (or right) halfantibody comprises a non-immunoglobulin based ABM and an Fc region. Thefirst and second half antibodies are associated through the Fc regionsforming an Fc domain.

In the embodiment of FIG. 11 , the first (or left) half antibodycomprises a Fab, an scFv, and an Fc region, and the second (or right)half antibody comprises a non-immunoglobulin based ABM and an Fc region.The first and second half antibodies are associated through the Fcregions forming an Fc domain.

In the embodiment of FIG. 1J, the first (or left) half antibodycomprises a Fab and an Fc region, and the second (or right) halfantibody comprises an scFv, a non-immunoglobulin based ABM and an Fcregion. The first and second half antibodies are associated through theFc regions forming an Fc domain.

In the embodiment of FIG. 1K, the first (or left) half antibodycomprises an scFv and an Fc region, and the second (or right) halfantibody comprises an scFv, an Fc region, and a second scFv. The firstand second half antibodies are associated through the Fc regions formingan Fc domain.

In the embodiment of FIG. 1N, the first (or left) half antibodycomprises a Fab, an Fc region, and an scFv, and the second (or right)half antibody comprises a Fab, and an Fc region. The first and secondhalf antibodies are associated through the Fc regions forming an Fcdomain.

In the embodiment of FIG. 10 , the first (or left) half antibodycomprises a Fab, an Fc region, and a scFab, and the second (or right)half antibody comprises a Fab and an Fc region. The first and secondhalf antibodies are associated through the Fc regions forming an Fcdomain.

In the embodiment of FIG. 1P, the first (or left) half antibodycomprises a Fab, a non-immunoglobulin based ABM, and an Fc region, andthe second (or right) half antibody comprises a scFv and an Fc region.The first and second half antibodies are associated through the Fcregions forming an Fc domain.

Alternatively, as depicted in FIG. 1L, trivalent a TBM can comprise twohalf antibodies, each comprising one complete ABM and a portion ofanother ABM (one a VH, the other a VL). The two half antibodies arepaired through an Fc domain, whereupon the VH and the VL associate toform a complete antigen-binding Fv domain.

The TBM can be a single chain, as shown in FIG. 1M. The TBM of FIG. 1Mcomprises three scFv domains connected through linkers.

In each of the configurations shown in FIGS. 1B-1P, each of the domainsdesignated X, Y, and Z represents an ABM1, ABM2, or ABM3, although notnecessarily in that order. In other words, X can be ABM1, ABM2, or ABM3,Y can be ABM1, ABM2, or ABM3, and Z can be ABM1, ABM2, or ABM3, providedthat the TBM comprises one ABM1, one ABM2, and one ABM3.

Accordingly, in the present disclosure provides a trivalent TBM as shownin any one of FIGS. 1B through 1P, where X is an ABM1, Y is an ABM3 andZ is an ABM2 (this configuration of ABMs designated as “T1” forconvenience).

The present disclosure also provides a trivalent TBM as shown in any oneof FIGS. 1B through 1P, where X is an ABM1, Y is an ABM2, and Z is anABM3 (this configuration of ABMs designated as “T2” for convenience).

The present disclosure further provides a trivalent TBM as shown in anyone of FIGS. 1B through 1P, where X is an ABM3, Y is an ABM1, and Z isan ABM2 (this configuration of ABMs designated as “T3” for convenience).

The present disclosure yet further provides a trivalent TBM as shown inany one of FIGS. 1B through 1P, where X is an ABM3, Y is an ABM2, and Zis an ABM1 (this configuration of ABMs designated as “T4” forconvenience).

The present disclosure yet further provides a trivalent TBM as shown inany one of FIGS. 1B through 1P, where X is an ABM2, Y is an ABM1, and Zis an ABM3 (this configuration of ABMs designated as “T5” forconvenience).

The present disclosure yet further provides a trivalent TBM as shown inany one of FIGS. 1B through 1P, where X is an ABM2, Y is an ABM3, and Zis an ABM1 (this configuration of ABMs designated as “T6” forconvenience).

7.4.2. Exemplary Tetravalent TBMs

The TBMs of the disclosure can be tetravalent, i.e., they have fourantigen-binding domains, one or two of which binds BCMA, one or two ofwhich binds a component of a TCR complex, and one or two of which bindsCD2 or a TAA.

Exemplary tetravalent TBM configurations are shown in FIGS. 1Q-1S.

As depicted in FIGS. 1Q-1S, a tetravalent TBM can comprise two halfantibodies, each comprising two complete ABMs, the two halves pairedthrough an Fc domain.

In the embodiment of FIG. 1Q, the first (or left) half antibodycomprises a Fab, an Fc region, and a second Fab, and the second (orright) half antibody comprises a Fab, an Fc region, and a second Fab.The first and second half antibodies are associated through the Fcregions forming an Fc domain.

In the embodiment of FIG. 1R, the first (or left) half antibodycomprises a Fab, an Fc region, and an scFv, and the second (or right)half antibody comprises a Fab, an Fc region, and an scFv. The first andsecond half antibodies are associated through the Fc regions forming anFc domain.

In the embodiment of FIG. 1S, the first (or left) half antibodycomprises a Fab, an Fc region, and an scFv, and the second (or right)half antibody comprises an scFv, an Fc region, and a Fab. The first andsecond half antibodies are associated through the Fc regions forming anFc domain.

In the configuration shown in FIGS. 1Q-1S, each of X, Y, Z, and Arepresent an ABM1, an ABM2, or an ABM3, although not necessarily in thatorder, and provided that the TBM comprises at least one ABM1, at leastone ABM2, and at least one ABM3. Thus, the tetravalent ABMs will includetwo ABMs against one of BCMA, a component of a TCR complex, and CD2 or aTAA. In some cases, a tetravalent TBM has two BCMA ABMs.

Accordingly, the present disclosure provides tetravalent TBMs as shownin any one of FIGS. 1Q-1S, where X, Y, Z, and A are ABMs directed toBCMA, a component of a TCR complex and CD2 or a TAA, as shown in Table8.

TABLE 8 ABM Permutations in Tetravalent TBMs Tetravalent Configuration XY Z A Tv 1 BCMA BCMA CD2 or TAA TCR Tv 2 BCMA BCMA TCR CD2 or TAA Tv 3BCMA CD2 or TAA BCMA TCR Tv 4 BCMA TCR BCMA CD2 or TAA Tv 5 BCMA CD2 orTAA TCR BCMA Tv 6 BCMA TCR CD2 or TAA BCMA Tv 7 CD2 or TAA BCMA BCMA TCRTv 8 TCR BCMA BCMA CD2 or TAA Tv 9 CD2 or TAA BCMA TCR BCMA Tv 10 TCRBCMA CD2 or TAA BCMA Tv 11 CD2 or TAA TCR BCMA BCMA Tv 12 TCR CD2 or TAABCMA BCMA Tv 13 BCMA CD2 or TAA TCR TCR Tv 14 BCMA TCR CD2 or TAA TCR Tv15 BCMA TCR TCR CD2 or TAA Tv 16 CD2 or TAA BCMA TCR TCR Tv 17 TCR BCMACD2 or TAA TCR Tv 18 TCR BCMA TCR CD2 or TAA Tv 19 CD2 or TAA TCR BCMATCR Tv 20 TCR CD2 or TAA BCMA TCR Tv 21 TCR TCR BCMA CD2 or TAA Tv 22CD2 or TAA TCR TCR BCMA Tv 23 TCR CD2 or TAA TCR BCMA Tv 24 TCR TCR CD2or TAA BCMA

7.4.3. Exemplary Pentavalent TBMs

The TBMs of the disclosure can be pentavalent, i.e., they have fiveantigen-binding domains, one, two, or three of which binds BCMA, one,two, or three of which binds a component of a TCR complex, and one, two,or three of which binds CD2 or a TAA.

An exemplary pentavalent TBM configuration is shown in FIG. 1T.

As depicted in FIG. 1T, a pentavalent TBM can comprise two halfantibodies, one of which comprises two complete ABMs and the other ofwhich comprises one complete ABM, the two halves paired through an Fcdomain.

In the embodiment of FIG. 1T, the first (or left) half antibodycomprises a Fab, an scFv, and an Fc region, and the second (or right)half antibody comprises a Fab, an Fc region, and an scFv. The first andsecond half antibodies are associated through the Fc regions forming anFc domain.

In the configuration shown in FIG. 1T, each of X, Y, Z, A, and Brepresent an ABM1, an ABM2, or an ABM3, although not necessarily in thatorder, and provided that the TBM comprises at least one ABM1, one ABM2,and one ABM3. Thus, the pentavalent TBMs can include two ABMs againsttwo of BCMA, a component of a TCR complex, and CD2 or a TAA, or threeABMs against one of BCMA, a component of a TCR complex, and CD2 or aTAA. In some cases, a pentavalent TBM has two or three BCMA ABMs. Insome embodiments, a pentavalent TBM has three ABM1s, one ABM2 and oneABM3.

Accordingly, the present disclosure provides a pentavalent TBM as shownin FIG. 1T, where X, Y, Z, A, and B are ABMs directed to BCMA, acomponent of a TCR complex, and CD2 or a TAA as shown in Table 9.

TABLE 9 ABM Permutations in Pentavalent TBMs Pentavalent Configuration XY Z A B Pv 1 BCMA BCMA BCMA CD2 or TAA TCR Pv 2 BCMA BCMA BCMA TCR CD2or TAA Pv 3 BCMA BCMA CD2 or TAA BCMA TCR Pv 4 BCMA BCMA TCR BCMA CD2 orTAA Pv 5 BCMA BCMA CD2 or TAA TCR BCMA Pv 6 BCMA BCMA TCR CD2 or TAABCMA Pv 7 BCMA CD2 or TAA BCMA BCMA TCR Pv 8 BCMA TCR BCMA BCMA CD2 orTAA Pv 9 BCMA CD2 or TAA BCMA TCR BCMA Pv 10 BCMA TCR BCMA CD2 or TAABCMA Pv 11 BCMA CD2 or TAA TCR BCMA BCMA Pv 12 BCMA TCR CD2 or TAA BCMABCMA Pv 13 CD2 or TAA BCMA BCMA BCMA TCR Pv 14 TCR BCMA BCMA BCMA CD2 orTAA Pv 15 CD2 or TAA BCMA BCMA TCR BCMA Pv 16 TCR BCMA BCMA CD2 or TAABCMA Pv 17 CD2 or TAA BCMA TCR BCMA BCMA Pv 18 TCR BCMA CD2 or TAA BCMABCMA Pv 19 CD2 or TAA TCR BCMA BCMA BCMA Pv 20 TCR CD2 or TAA BCMA BCMABCMA Pv 21 BCMA BCMA CD2 or TAA CD2 or TAA TCR Pv 22 BCMA BCMA CD2 orTAA TCR CD2 or TAA Pv 23 BCMA BCMA TCR CD2 or TAA CD2 or TAA Pv 24 BCMACD2 or TAA BCMA CD2 or TAA TCR Pv 25 BCMA CD2 or TAA BCMA TCR CD2 or TAAPv 26 BCMA TCR BCMA CD2 or TAA CD2 or TAA Pv 27 BCMA CD2 or TAA CD2 orTAA BCMA TCR Pv 28 BCMA CD2 or TAA TCR BCMA CD2 or TAA Pv 29 BCMA TCRCD2 or TAA BCMA CD2 or TAA Pv 30 BCMA CD2 or TAA CD2 or TAA TCR BCMA Pv31 BCMA CD2 or TAA TCR CD2 or TAA BCMA Pv 32 BCMA TCR CD2 or TAA CD2 orTAA BCMA Pv 33 CD2 or TAA BCMA BCMA CD2 or TAA TCR Pv 34 CD2 or TAA BCMABCMA TCR CD2 or TAA Pv 35 TCR BCMA BCMA CD2 or TAA CD2 or TAA Pv 36 CD2or TAA BCMA CD2 or TAA BCMA TCR Pv 37 CD2 or TAA BCMA TCR BCMA CD2 orTAA Pv 38 TCR BCMA CD2 or TAA BCMA CD2 or TAA Pv 39 CD2 or TAA BCMA CD2or TAA TCR BCMA Pv 40 CD2 or TAA BCMA TCR CD2 or TAA BCMA Pv 41 TCR BCMACD2 or TAA CD2 or TAA BCMA Pv 42 CD2 or TAA CD2 or TAA BCMA BCMA TCR Pv43 CD2 or TAA TCR BCMA BCMA CD2 or TAA Pv 44 TCR CD2 or TAA BCMA BCMACD2 or TAA Pv 45 CD2 or TAA CD2 or TAA BCMA TCR BCMA Pv 46 CD2 or TAATCR BCMA CD2 or TAA BCMA Pv 47 TCR CD2 or TAA BCMA CD2 or TAA BCMA Pv 48CD2 or TAA CD2 or TAA TCR BCMA BCMA Pv 49 CD2 or TAA TCR CD2 or TAA BCMABCMA Pv 50 TCR CD2 or TAA CD2 or TAA BCMA BCMA Pv 51 BCMA BCMA CD2 orTAA TCR TCR Pv 52 BCMA BCMA TCR CD2 or TAA TCR Pv 53 BCMA BCMA TCR TCRCD2 or TAA Pv 54 BCMA CD2 or TAA BCMA TCR TCR Pv 55 BCMA TCR BCMA CD2 orTAA TCR Pv 56 BCMA TCR BCMA TCR CD2 or TAA Pv 57 BCMA CD2 or TAA TCRBCMA TCR Pv 58 BCMA TCR CD2 or TAA BCMA TCR Pv 59 BCMA TCR TCR BCMA CD2or TAA Pv 60 BCMA CD2 or TAA TCR TCR BCMA Pv 61 BCMA TCR CD2 or TAA TCRBCMA Pv 62 BCMA TCR TCR CD2 or TAA BCMA Pv 63 CD2 or TAA BCMA BCMA TCRTCR Pv 64 TCR BCMA BCMA CD2 or TAA TCR Pv 65 TCR BCMA BCMA TCR CD2 orTAA Pv 66 CD2 or TAA BCMA TCR BCMA TCR Pv 67 TCR BCMA CD2 or TAA BCMATCR Pv 68 TCR BCMA TCR BCMA CD2 or TAA Pv 69 CD2 or TAA BCMA TCR TCRBCMA Pv 70 TCR BCMA CD2 or TAA TCR BCMA Pv 71 TCR BCMA TCR CD2 or TAABCMA Pv 72 CD2 or TAA TCR BCMA BCMA TCR Pv 73 TCR CD2 or TAA BCMA BCMATCR Pv 74 TCR TCR BCMA BCMA CD2 or TAA Pv 75 CD2 or TAA TCR BCMA TCRBCMA Pv 76 TCR CD2 or TAA BCMA TCR BCMA Pv 77 TCR TCR BCMA CD2 or TAABCMA Pv 78 CD2 or TAA TCR TCR BCMA BCMA Pv 79 TCR CD2 or TAA TCR BCMABCMA Pv 80 TCR TCR CD2 or TAA BCMA BCMA Pv 81 BCMA CD2 or TAA TCR TCRTCR Pv 82 BCMA TCR CD2 or TAA TCR TCR Pv 83 BCMA TCR TCR CD2 or TAA TCRPv 84 BCMA TCR TCR TCR CD2 or TAA Pv 85 CD2 or TAA BCMA TCR TCR TCR Pv86 TCR BCMA CD2 or TAA TCR TCR Pv 87 TCR BCMA TCR CD2 or TAA TCR Pv 88TCR BCMA TCR TCR CD2 or TAA Pv 89 CD2 or TAA TCR BCMA TCR TCR Pv 90 TCRCD2 or TAA BCMA TCR TCR Pv 91 TCR TCR BCMA CD2 or TAA TCR Pv 92 TCR TCRBCMA TCR CD2 or TAA Pv 93 CD2 or TAA TCR TCR BCMA TCR Pv 94 TCR CD2 orTAA TCR BCMA TCR Pv 95 TCR TCR CD2 or TAA BCMA TCR Pv 96 TCR TCR TCRBCMA CD2 or TAA Pv 97 CD2 or TAA TCR TCR TCR BCMA Pv 98 TCR CD2 or TAATCR TCR BCMA Pv 99 TCR TCR CD2 or TAA TCR BCMA Pv 100 TCR TCR TCR CD2 orTAA BCMA

7.4.4. Exemplary Hexavalent TBMs

The TBMs of the disclosure can be hexavalent, i.e., they have sixantigen-binding domains, one, two, three, or four of which binds BCMA,one, two, three, or four of which binds a component of a TCR complex,and one, two, three, or four of which binds CD2 or a TAA.

Exemplary hexavalent TBM configurations are shown in FIGS. 1U-1V.

As depicted in FIGS. 1U-1V, a pentavalent TBM can comprise two halfantibodies, one of which comprises two complete ABMs and the other ofwhich comprises one complete ABM, the two halves paired through an Fcdomain.

In the embodiment of FIG. 1U, the first (or left) half antibodycomprises a Fab, a second Fab, an Fc region, and an scFv, and the second(or right) half antibody comprises a Fab, a second Fab, an Fc region,and an scFv. The first and second half antibodies are associated throughthe Fc regions forming an Fc domain.

In the embodiment of FIG. 1V, the first (or left) half antibodycomprises a first Fv, a second Fv, a third Fv, and an Fc region, and thesecond (or right) half antibody comprises a first Fv, a second Fv, athird Fv, and an Fc region. The first and second half antibodies areassociated through the Fc regions forming an Fc domain.

In the configuration shown in FIGS. 1U-1V, each of X, Y, Z, A, B, and Crepresent an ABM1, an ABM2, or an ABM3, although not necessarily in thatorder, and provided that the TBM comprises at least one ABM1, one ABM2,and one ABM3. Thus, the hexavalent TBMs can include (i) two ABMs againsteach of BCMA, a component of a TCR complex, and CD2 or a TAA, (ii) threeABMs against one of BCMA, a component of a TCR complex, and CD2 or aTAA, or (iii) four ABMs against one of BCMA, a component of a TCRcomplex, and CD2 or a TAA. For example, a hexavalent ABM can includethree ABMs against BCMA, two ABMs against CD2 or a TAA and one ABMagainst a component of a TCR complex. As another example, a hexavalentABM can include three ABMs against BCMA, two ABMs against a component ofa TCR complex and one ABM against CD2 or a TAA. In some cases, ahexavalent TBM has two, three, our four BCMA ABMs. In some embodiments,a hexavalent TBM has three BCMA ABMs. In other embodiments, a hexavalentTBM has four BCMA ABMs.

Accordingly, in the present disclosure provides hexavalent TBMs as shownin any one of FIGS. 1U-1V, where X, Y, Z, A, B, and C are ABMs directedto BCMA, a component of a TCR complex, and CD2 or a TAA, as shown inTable 10.

TABLE 10 ABM Permutations in Hexavalent TBMs Hexavalent Configuration XY Z A B C Hv 1 BCMA BCMA BCMA BCMA CD2 or TCR TAA Hv 2 BCMA BCMA BCMABCMA TCR CD2 or TAA Hv 3 BCMA BCMA BCMA CD2 or BCMA TCR TAA Hv 4 BCMABCMA BCMA TCR BCMA CD2 or TAA Hv 5 BCMA BCMA BCMA CD2 or TCR BCMA TAA Hv6 BCMA BCMA BCMA TCR CD2 or BCMA TAA Hv 7 BCMA BCMA CD2 or BCMA BCMA TCRTAA Hv 8 BCMA BCMA TCR BCMA BCMA CD2 or TAA Hv 9 BCMA BCMA CD2 or BCMATCR BCMA TAA Hv 10 BCMA BCMA TCR BCMA CD2 or BCMA TAA Hv 11 BCMA BCMACD2 or TCR BCMA BCMA TAA Hv 12 BCMA BCMA TCR CD2 or BCMA BCMA TAA Hv 13BCMA CD2 or BCMA BCMA BCMA TCR TAA Hv 14 BCMA TCR BCMA BCMA BCMA CD2 orTAA Hv 15 BCMA CD2 or BCMA BCMA TCR BCMA TAA Hv 16 BCMA TCR BCMA BCMACD2 or BCMA TAA Hv 17 BCMA CD2 or BCMA TCR BCMA BCMA TAA Hv 18 BCMA TCRBCMA CD2 or BCMA BCMA TAA Hv 19 BCMA CD2 or TCR BCMA BCMA BCMA TAA Hv 20BCMA TCR CD2 or BCMA BCMA BCMA TAA Hv 21 CD2 or BCMA BCMA BCMA BCMA TCRTAA Hv 22 TCR BCMA BCMA BCMA BCMA CD2 or TAA Hv 23 CD2 or BCMA BCMA BCMATCR BCMA TAA Hv 24 TCR BCMA BCMA BCMA CD2 or BCMA TAA Hv 25 CD2 or BCMABCMA TCR BCMA BCMA TAA Hv 26 TCR BCMA BCMA CD2 or BCMA BCMA TAA Hv 27CD2 or BCMA TCR BCMA BCMA BCMA TAA Hv 28 TCR BCMA CD2 or BCMA BCMA BCMATAA Hv 29 CD2 or TCR BCMA BCMA BCMA BCMA TAA Hv 30 TCR CD2 or BCMA BCMABCMA BCMA TAA Hv 31 BCMA BCMA BCMA CD2 or CD2 or TCR TAA TAA Hv 32 BCMABCMA BCMA CD2 or TCR CD2 or TAA TAA Hv 33 BCMA BCMA BCMA TCR CD2 or CD2or TAA TAA Hv 34 BCMA BCMA CD2 or BCMA CD2 or TCR TAA TAA Hv 35 BCMABCMA CD2 or BCMA TCR CD2 or TAA TAA Hv 36 BCMA BCMA TCR BCMA CD2 or CD2or TAA TAA Hv 37 BCMA BCMA CD2 or CD2 or BCMA TCR TAA TAA Hv 38 BCMABCMA CD2 or TCR BCMA CD2 or TAA TAA Hv 39 BCMA BCMA TCR CD2 or BCMA CD2or TAA TAA Hv 40 BCMA BCMA CD2 or CD2 or TCR BCMA TAA TAA Hv 41 BCMABCMA CD2 or TCR CD2 or BCMA TAA TAA Hv 42 BCMA BCMA TCR CD2 or CD2 orBCMA TAA TAA Hv 43 BCMA CD2 or BCMA BCMA CD2 or TCR TAA TAA Hv 44 BCMACD2 or BCMA BCMA TCR CD2 or TAA TAA Hv 45 BCMA TCR BCMA BCMA CD2 or CD2or TAA TAA Hv 46 BCMA CD2 or BCMA CD2 or BCMA TCR TAA TAA Hv 47 BCMA CD2or BCMA TCR BCMA CD2 or TAA TAA Hv 48 BCMA TCR BCMA CD2 or BCMA CD2 orTAA TAA Hv 49 BCMA CD2 or BCMA CD2 or TCR BCMA TAA TAA Hv 50 BCMA CD2 orBCMA TCR CD2 or BCMA TAA TAA Hv 51 BCMA TCR BCMA CD2 or CD2 or BCMA TAATAA Hv 52 BCMA CD2 or CD2 or BCMA BCMA TCR TAA TAA Hv 53 BCMA CD2 or TCRBCMA BCMA CD2 or TAA TAA Hv 54 BCMA TCR CD2 or BCMA BCMA CD2 or TAA TAAHv 55 BCMA CD2 or CD2 or BCMA TCR BCMA TAA TAA Hv 56 BCMA CD2 or TCRBCMA CD2 or BCMA TAA TAA Hv 57 BCMA TCR CD2 or BCMA CD2 or BCMA TAA TAAHv 58 BCMA CD2 or CD2 or TCR BCMA BCMA TAA TAA Hv 59 BCMA CD2 or TCR CD2or BCMA BCMA TAA TAA Hv 60 BCMA TCR CD2 or CD2 or BCMA BCMA TAA TAA Hv61 CD2 or BCMA BCMA BCMA CD2 or TCR TAA TAA Hv 62 CD2 or BCMA BCMA BCMATCR CD2 or TAA TAA Hv 63 TCR BCMA BCMA BCMA CD2 or CD2 or TAA TAA Hv 64CD2 or BCMA BCMA CD2 or BCMA TCR TAA TAA Hv 65 CD2 or BCMA BCMA TCR BCMACD2 or TAA TAA Hv 66 TCR BCMA BCMA CD2 or BCMA CD2 or TAA TAA Hv 67 CD2or BCMA BCMA CD2 or TCR BCMA TAA TAA Hv 68 CD2 or BCMA BCMA TCR CD2 orBCMA TAA TAA Hv 69 TCR BCMA BCMA CD2 or CD2 or BCMA TAA TAA Hv 70 CD2 orBCMA CD2 or BCMA BCMA TCR TAA TAA Hv 71 CD2 or BCMA TCR BCMA BCMA CD2 orTAA TAA Hv 72 TCR BCMA CD2 or BCMA BCMA CD2 or TAA TAA Hv 73 CD2 or BCMACD2 or BCMA TCR BCMA TAA TAA Hv 74 CD2 or BCMA TCR BCMA CD2 or BCMA TAATAA Hv 75 TCR BCMA CD2 or BCMA CD2 or BCMA TAA TAA Hv 76 CD2 or BCMA CD2or TCR BCMA BCMA TAA TAA Hv 77 CD2 or BCMA TCR CD2 or BCMA BCMA TAA TAAHv 78 TCR BCMA CD2 or CD2 or BCMA BCMA TAA TAA Hv 79 CD2 or CD2 or BCMABCMA BCMA TCR TAA TAA Hv 80 CD2 or TCR BCMA BCMA BCMA CD2 or TAA TAA Hv81 TCR CD2 or BCMA BCMA BCMA CD2 or TAA TAA Hv 82 CD2 or CD2 or BCMABCMA TCR BCMA TAA TAA Hv 83 CD2 or TCR BCMA BCMA CD2 or BCMA TAA TAA Hv84 TCR CD2 or BCMA BCMA CD2 or BCMA TAA TAA Hv 85 CD2 or CD2 or BCMA TCRBCMA BCMA TAA TAA Hv 86 CD2 or TCR BCMA CD2 or BCMA BCMA TAA TAA Hv 87TCR CD2 or BCMA CD2 or BCMA BCMA TAA TAA Hv 88 CD2 or CD2 or TCR BCMABCMA BCMA TAA TAA Hv 89 CD2 or TCR CD2 or BCMA BCMA BCMA TAA TAA Hv 90TCR CD2 or CD2 or BCMA BCMA BCMA TAA TAA Hv 91 BCMA BCMA BCMA CD2 or TCRTCR TAA Hv 92 BCMA BCMA BCMA TCR CD2 or TCR TAA Hv 93 BCMA BCMA BCMA TCRTCR CD2 or TAA Hv 94 BCMA BCMA CD2 or BCMA TCR TCR TAA Hv 95 BCMA BCMATCR BCMA CD2 or TCR TAA Hv 96 BCMA BCMA TCR BCMA TCR CD2 or TAA Hv 97BCMA BCMA CD2 or TCR BCMA TCR TAA Hv 98 BCMA BCMA TCR CD2 or BCMA TCRTAA Hv 99 BCMA BCMA TCR TCR BCMA CD2 or TAA Hv 100 BCMA BCMA CD2 or TCRTCR BCMA TAA Hv 101 BCMA BCMA TCR CD2 or TCR BCMA TAA Hv 102 BCMA BCMATCR TCR CD2 or BCMA TAA Hv 103 BCMA CD2 or BCMA BCMA TCR TCR TAA Hv 104BCMA TCR BCMA BCMA CD2 or TCR TAA Hv 105 BCMA TCR BCMA BCMA TCR CD2 orTAA Hv 106 BCMA CD2 or BCMA TCR BCMA TCR TAA Hv 107 BCMA TCR BCMA CD2 orBCMA TCR TAA Hv 108 BCMA TCR BCMA TCR BCMA CD2 or TAA Hv 109 BCMA CD2 orBCMA TCR TCR BCMA TAA Hv 110 BCMA TCR BCMA CD2 or TCR BCMA TAA Hv 111BCMA TCR BCMA TCR CD2 or BCMA TAA Hv 112 BCMA CD2 or TCR BCMA BCMA TCRTAA Hv 113 BCMA TCR CD2 or BCMA BCMA TCR TAA Hv 114 BCMA TCR TCR BCMABCMA CD2 or TAA Hv 115 BCMA CD2 or TCR BCMA TCR BCMA TAA Hv 116 BCMA TCRCD2 or BCMA TCR BCMA TAA Hv 117 BCMA TCR TCR BCMA CD2 or BCMA TAA Hv 118BCMA CD2 or TCR TCR BCMA BCMA TAA Hv 119 BCMA TCR CD2 or TCR BCMA BCMATAA Hv 120 BCMA TCR TCR CD2 or BCMA BCMA TAA Hv 121 CD2 or BCMA BCMABCMA TCR TCR TAA Hv 122 TCR BCMA BCMA BCMA CD2 or TCR TAA Hv 123 TCRBCMA BCMA BCMA TCR CD2 or TAA Hv 124 CD2 or BCMA BCMA TCR BCMA TCR TAAHv 125 TCR BCMA BCMA CD2 or BCMA TCR TAA Hv 126 TCR BCMA BCMA TCR BCMACD2 or TAA Hv 127 CD2 or BCMA BCMA TCR TCR BCMA TAA Hv 128 TCR BCMA BCMACD2 or TCR BCMA TAA Hv 129 TCR BCMA BCMA TCR CD2 or BCMA TAA Hv 130 CD2or BCMA TCR BCMA BCMA TCR TAA Hv 131 TCR BCMA CD2 or BCMA BCMA TCR TAAHv 132 TCR BCMA TCR BCMA BCMA CD2 or TAA Hv 133 CD2 or BCMA TCR BCMA TCRBCMA TAA Hv 134 TCR BCMA CD2 or BCMA TCR BCMA TAA Hv 135 TCR BCMA TCRBCMA CD2 or BCMA TAA Hv 136 CD2 or BCMA TCR TCR BCMA BCMA TAA Hv 137 TCRBCMA CD2 or TCR BCMA BCMA TAA Hv 138 TCR BCMA TCR CD2 or BCMA BCMA TAAHv 139 CD2 or TCR BCMA BCMA BCMA TCR TAA Hv 140 TCR CD2 or BCMA BCMABCMA TCR TAA Hv 141 TCR TCR BCMA BCMA BCMA CD2 or TAA Hv 142 CD2 or TCRBCMA BCMA TCR BCMA TAA Hv 143 TCR CD2 or BCMA BCMA TCR BCMA TAA Hv 144TCR TCR BCMA BCMA CD2 or BCMA TAA Hv 145 CD2 or TCR BCMA TCR BCMA BCMATAA Hv 146 TCR CD2 or BCMA TCR BCMA BCMA TAA Hv 147 TCR TCR BCMA CD2 orBCMA BCMA TAA Hv 148 CD2 or TCR TCR BCMA BCMA BCMA TAA Hv 149 TCR CD2 orTCR BCMA BCMA BCMA TAA Hv 150 TCR TCR CD2 or BCMA BCMA BCMA TAA Hv 151BCMA BCMA CD2 or CD2 or TCR TCR TAA TAA Hv 152 BCMA BCMA CD2 or TCR CD2or TCR TAA TAA Hv 153 BCMA BCMA CD2 or TCR TCR CD2 or TAA TAA Hv 154BCMA BCMA TCR CD2 or CD2 or TCR TAA TAA Hv 155 BCMA BCMA TCR CD2 or TCRCD2 or TAA TAA Hv 156 BCMA BCMA TCR TCR CD2 or CD2 or TAA TAA Hv 157BCMA CD2 or BCMA CD2 or TCR TCR TAA TAA Hv 158 BCMA CD2 or BCMA TCR CD2or TCR TAA TAA Hv 159 BCMA CD2 or BCMA TCR TCR CD2 or TAA TAA Hv 160BCMA TCR BCMA CD2 or CD2 or TCR TAA TAA Hv 161 BCMA TCR BCMA CD2 or TCRCD2 or TAA TAA Hv 162 BCMA TCR BCMA TCR CD2 or CD2 or TAA TAA Hv 163BCMA CD2 or CD2 or BCMA TCR TCR TAA TAA Hv 164 BCMA CD2 or TCR BCMA CD2or TCR TAA TAA Hv 165 BCMA CD2 or TCR BCMA TCR CD2 or TAA TAA Hv 166BCMA TCR CD2 or BCMA CD2 or TCR TAA TAA Hv 167 BCMA TCR CD2 or BCMA TCRCD2 or TAA TAA Hv 168 BCMA TCR TCR BCMA CD2 or CD2 or TAA TAA Hv 169BCMA CD2 or CD2 or TCR BCMA TCR TAA TAA Hv 170 BCMA CD2 or TCR CD2 orBCMA TCR TAA TAA Hv 171 BCMA CD2 or TCR TCR BCMA CD2 or TAA TAA Hv 172BCMA TCR CD2 or CD2 or BCMA TCR TAA TAA Hv 173 BCMA TCR CD2 or TCR BCMACD2 or TAA TAA Hv 174 BCMA TCR TCR CD2 or BCMA CD2 or TAA TAA Hv 175BCMA CD2 or CD2 or TCR TCR BCMA TAA TAA Hv 176 BCMA CD2 or TCR CD2 orTCR BCMA TAA TAA Hv 177 BCMA CD2 or TCR TCR CD2 or BCMA TAA TAA Hv 178BCMA TCR CD2 or CD2 or TCR BCMA TAA TAA Hv 179 BCMA TCR CD2 or TCR CD2or BCMA TAA TAA Hv 180 BCMA TCR TCR CD2 or CD2 or BCMA TAA TAA Hv 181CD2 or BCMA BCMA CD2 or TCR TCR TAA TAA Hv 182 CD2 or BCMA BCMA TCR CD2or TCR TAA TAA Hv 183 CD2 or BCMA BCMA TCR TCR CD2 or TAA TAA Hv 184 TCRBCMA BCMA CD2 or CD2 or TCR TAA TAA Hv 185 TCR BCMA BCMA CD2 or TCR CD2or TAA TAA Hv 186 TCR BCMA BCMA TCR CD2 or CD2 or TAA TAA Hv 187 CD2 orBCMA CD2 or BCMA TCR TCR TAA TAA Hv 188 CD2 or BCMA TCR BCMA CD2 or TCRTAA TAA Hv 189 CD2 or BCMA TCR BCMA TCR CD2 or TAA TAA Hv 190 TCR BCMACD2 or BCMA CD2 or TCR TAA TAA Hv 191 TCR BCMA CD2 or BCMA TCR CD2 orTAA TAA Hv 192 TCR BCMA TCR BCMA CD2 or CD2 or TAA TAA Hv 193 CD2 orBCMA CD2 or TCR BCMA TCR TAA TAA Hv 194 CD2 or BCMA TCR CD2 or BCMA TCRTAA TAA Hv 195 CD2 or BCMA TCR TCR BCMA CD2 or TAA TAA Hv 196 TCR BCMACD2 or CD2 or BCMA TCR TAA TAA Hv 197 TCR BCMA CD2 or TCR BCMA CD2 orTAA TAA Hv 198 TCR BCMA TCR CD2 or BCMA CD2 or TAA TAA Hv 199 CD2 orBCMA CD2 or TCR TCR BCMA TAA TAA Hv 200 CD2 or BCMA TCR CD2 or TCR BCMATAA TAA Hv 201 CD2 or BCMA TCR TCR CD2 or BCMA TAA TAA Hv 202 TCR BCMACD2 or CD2 or TCR BCMA TAA TAA Hv 203 TCR BCMA CD2 or TCR CD2 or BCMATAA TAA Hv 204 TCR BCMA TCR CD2 or CD2 or BCMA TAA TAA Hv 205 CD2 or CD2or BCMA BCMA TCR TCR TAA TAA Hv 206 CD2 or TCR BCMA BCMA CD2 or TCR TAATAA Hv 207 CD2 or TCR BCMA BCMA TCR CD2 or TAA TAA Hv 208 TCR CD2 orBCMA BCMA CD2 or TCR TAA TAA Hv 209 TCR CD2 or BCMA BCMA TCR CD2 or TAATAA Hv 210 TCR TCR BCMA BCMA CD2 or CD2 or TAA TAA Hv 211 CD2 or CD2 orBCMA TCR BCMA TCR TAA TAA Hv 212 CD2 or TCR BCMA CD2 or BCMA TCR TAA TAAHv 213 CD2 or TCR BCMA TCR BCMA CD2 or TAA TAA Hv 214 TCR CD2 or BCMACD2 or BCMA TCR TAA TAA Hv 215 TCR CD2 or BCMA TCR BCMA CD2 or TAA TAAHv 216 TCR TCR BCMA CD2 or BCMA CD2 or TAA TAA Hv 217 CD2 or CD2 or BCMATCR TCR BCMA TAA TAA Hv 218 CD2 or TCR BCMA CD2 or TCR BCMA TAA TAA Hv219 CD2 or TCR BCMA TCR CD2 or BCMA TAA TAA Hv 220 TCR CD2 or BCMA CD2or TCR BCMA TAA TAA Hv 221 TCR CD2 or BCMA TCR CD2 or BCMA TAA TAA Hv222 TCR TCR BCMA CD2 or CD2 or BCMA TAA TAA Hv 223 CD2 or CD2 or TCRBCMA BCMA TCR TAA TAA Hv 224 CD2 or TCR CD2 or BCMA BCMA TCR TAA TAA Hv225 CD2 or TCR TCR BCMA BCMA CD2 or TAA TAA Hv 226 TCR CD2 or CD2 orBCMA BCMA TCR TAA TAA Hv 227 TCR CD2 or TCR BCMA BCMA CD2 or TAA TAA Hv228 TCR TCR CD2 or BCMA BCMA CD2 or TAA TAA Hv 229 CD2 or CD2 or TCRBCMA TCR BCMA TAA TAA Hv 230 CD2 or TCR CD2 or BCMA TCR BCMA TAA TAA Hv231 CD2 or TCR TCR BCMA CD2 or BCMA TAA TAA Hv 232 TCR CD2 or CD2 orBCMA TCR BCMA TAA TAA Hv 233 TCR CD2 or TCR BCMA CD2 or BCMA TAA TAA Hv234 TCR TCR CD2 or BCMA CD2 or BCMA TAA TAA Hv 235 CD2 or CD2 or TCR TCRBCMA BCMA TAA TAA Hv 236 CD2 or TCR CD2 or TCR BCMA BCMA TAA TAA Hv 237CD2 or TCR TCR CD2 or BCMA BCMA TAA TAA Hv 238 TCR CD2 or CD2 or TCRBCMA BCMA TAA TAA Hv 239 TCR CD2 or TCR CD2 or BCMA BCMA TAA TAA Hv 240TCR TCR CD2 or CD2 or BCMA BCMA TAA TAA Hv 241 BCMA BCMA CD2 or TCR TCRTCR TAA Hv 242 BCMA BCMA TCR CD2 or TCR TCR TAA Hv 243 BCMA BCMA TCR TCRCD2 or TCR TAA Hv 244 BCMA BCMA TCR TCR TCR CD2 or TAA Hv 245 BCMA CD2or BCMA TCR TCR TCR TAA Hv 246 BCMA TCR BCMA CD2 or TCR TCR TAA Hv 247BCMA TCR BCMA TCR CD2 or TCR TAA Hv 248 BCMA TCR BCMA TCR TCR CD2 or TAAHv 249 BCMA CD2 or TCR BCMA TCR TCR TAA Hv 250 BCMA TCR CD2 or BCMA TCRTCR TAA Hv 251 BCMA TCR TCR BCMA CD2 or TCR TAA Hv 252 BCMA TCR TCR BCMATCR CD2 or TAA Hv 253 BCMA CD2 or TCR TCR BCMA TCR TAA Hv 254 BCMA TCRCD2 or TCR BCMA TCR TAA Hv 255 BCMA TCR TCR CD2 or BCMA TCR TAA Hv 256BCMA TCR TCR TCR BCMA CD2 or TAA Hv 257 BCMA CD2 or TCR TCR TCR BCMA TAAHv 258 BCMA TCR CD2 or TCR TCR BCMA TAA Hv 259 BCMA TCR TCR CD2 or TCRBCMA TAA Hv 260 BCMA TCR TCR TCR CD2 or BCMA TAA Hv 261 CD2 or BCMA BCMATCR TCR TCR TAA Hv 262 TCR BCMA BCMA CD2 or TCR TCR TAA Hv 263 TCR BCMABCMA TCR CD2 or TCR TAA Hv 264 TCR BCMA BCMA TCR TCR CD2 or TAA Hv 265CD2 or BCMA TCR BCMA TCR TCR TAA Hv 266 TCR BCMA CD2 or BCMA TCR TCR TAAHv 267 TCR BCMA TCR BCMA CD2 or TCR TAA Hv 268 TCR BCMA TCR BCMA TCR CD2or TAA Hv 269 CD2 or BCMA TCR TCR BCMA TCR TAA Hv 270 TCR BCMA CD2 orTCR BCMA TCR TAA Hv 271 TCR BCMA TCR CD2 or BCMA TCR TAA Hv 272 TCR BCMATCR TCR BCMA CD2 or TAA Hv 273 CD2 or BCMA TCR TCR TCR BCMA TAA Hv 274TCR BCMA CD2 or TCR TCR BCMA TAA Hv 275 TCR BCMA TCR CD2 or TCR BCMA TAAHv 276 TCR BCMA TCR TCR CD2 or BCMA TAA Hv 277 CD2 or TCR BCMA BCMA TCRTCR TAA Hv 278 TCR CD2 or BCMA BCMA TCR TCR TAA Hv 279 TCR TCR BCMA BCMACD2 or TCR TAA Hv 280 TCR TCR BCMA BCMA TCR CD2 or TAA Hv 281 CD2 or TCRBCMA TCR BCMA TCR TAA Hv 282 TCR CD2 or BCMA TCR BCMA TCR TAA Hv 283 TCRTCR BCMA CD2 or BCMA TCR TAA Hv 284 TCR TCR BCMA TCR BCMA CD2 or TAA Hv285 CD2 or TCR BCMA TCR TCR BCMA TAA Hv 286 TCR CD2 or BCMA TCR TCR BCMATAA Hv 287 TCR TCR BCMA CD2 or TCR BCMA TAA Hv 288 TCR TCR BCMA TCR CD2or BCMA TAA Hv 289 CD2 or TCR TCR BCMA BCMA TCR TAA Hv 290 TCR CD2 orTCR BCMA BCMA TCR TAA Hv 291 TCR TCR CD2 or BCMA BCMA TCR TAA Hv 292 TCRTCR TCR BCMA BCMA CD2 or TAA Hv 293 CD2 or TCR TCR BCMA TCR BCMA TAA Hv294 TCR CD2 or TCR BCMA TCR BCMA TAA Hv 295 TCR TCR CD2 or BCMA TCR BCMATAA Hv 296 TCR TCR TCR BCMA CD2 or BCMA TAA Hv 297 CD2 or TCR TCR TCRBCMA BCMA TAA Hv 298 TCR CD2 or TCR TCR BCMA BCMA TAA Hv 299 TCR TCR CD2or TCR BCMA BCMA TAA Hv 300 TCR TCR TCR CD2 or BCMA BCMA TAA Hv 301 BCMACD2 or TCR TCR TCR TCR TAA Hv 302 BCMA TCR CD2 or TCR TCR TCR TAA Hv 303BCMA TCR TCR CD2 or TCR TCR TAA Hv 304 BCMA TCR TCR TCR CD2 or TCR TAAHv 305 BCMA TCR TCR TCR TCR CD2 or TAA Hv 306 CD2 or BCMA TCR TCR TCRTCR TAA Hv 307 TCR BCMA CD2 or TCR TCR TCR TAA Hv 308 TCR BCMA TCR CD2or TCR TCR TAA Hv 309 TCR BCMA TCR TCR CD2 or TCR TAA Hv 310 TCR BCMATCR TCR TCR CD2 or TAA Hv 311 CD2 or TCR BCMA TCR TCR TCR TAA Hv 312 TCRCD2 or BCMA TCR TCR TCR TAA Hv 313 TCR TCR BCMA CD2 or TCR TCR TAA Hv314 TCR TCR BCMA TCR CD2 or TCR TAA Hv 315 TCR TCR BCMA TCR TCR CD2 orTAA Hv 316 CD2 or TCR TCR BCMA TCR TCR TAA Hv 317 TCR CD2 or TCR BCMATCR TCR TAA Hv 318 TCR TCR CD2 or BCMA TCR TCR TAA Hv 319 TCR TCR TCRBCMA CD2 or TCR TAA Hv 320 TCR TCR TCR BCMA TCR CD2 or TAA Hv 321 CD2 orTCR TCR TCR BCMA TCR TAA Hv 322 TCR CD2 or TCR TCR BCMA TCR TAA Hv 323TCR TCR CD2 or TCR BCMA TCR TAA Hv 324 TCR TCR TCR CD2 or BCMA TCR TAAHv 325 TCR TCR TCR TCR BCMA CD2 or TAA Hv 326 CD2 or TCR TCR TCR TCRBCMA TAA Hv 327 TCR CD2 or TCR TCR TCR BCMA TAA Hv 328 TCR TCR CD2 orTCR TCR BCMA TAA Hv 329 TCR TCR TCR CD2 or TCR BCMA TAA Hv 330 TCR TCRTCR TCR CD2 or BCMA TAA

7.5. BCMA ABMs

The MBMs (e.g., TBMs) contain an ABM (ABM1) that specifically binds tohuman BCMA. BCMA is a tumor necrosis family receptor (TNFR) memberexpressed on cells of the B-cell lineage. BCMA expression is the higheston terminally differentiated B cells that assume the long lived plasmacell fate, including plasma cells, plasmablasts and a subpopulation ofactivated B cells and memory B cells. BCMA is involved in mediating thesurvival of plasma cells for maintaining long-term humoral immunity. Theexpression of BCMA has been recently linked to a number of cancers,autoimmune disorders, and infectious diseases. Cancers with increasedexpression of BCMA include some hematological cancers, such as multiplemyeloma, Hodgkin's and non-Hodgkin's lymphoma, various leukemias, andglioblastoma.

ABM1 can comprise, for example, an anti-BCMA antibody or anantigen-binding domain thereof. The anti-BCMA antibody orantigen-binding domain thereof can comprise, for example, CDR, VH, VL,or scFV sequences set forth in Tables 11A-1 to 11P (collectively “Table11”).

TABLE 11A-1 AB1/AB2 Family Light Chain CDR Consensus sequences SEQ IDSEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: C1 RASQSISSYLN 79AASSLQS 82 QQSYSXPLT 84 (AB1/AB2 (X = S or T) consensus- Kabat) C2RASQSISSYLN 79 AASSLQS 82 QQSYX₁X₂PX₃T 85 (AB1/AB2 (X₁ = S, G, D, Y, orfamily A; X₂ = S, T, or A; consensus- X₃ = P or L) Kabat) C3 SQSISSY 80AAS 83 SYSXPL 86 (AB1/AB2 (X = S or T) consensus- Chothia) C4 SQSISSY 80AAS 83 SYX₁X₂PX₃ 87 (AB1/AB2 (X₁ = S, G, D, Y, OR familyA; X₂ = S, T, OR A; consensus- X₃ = P OR L) Chothia) C5 QSISSY 81 AAS 83QQSYSXPLT 84 (AB1/AB2 (X = S OR T) consensus- IMGT) C6 QSISSY 81 AAS 83QQSYX₁X₂PX₃T 85 (AB1/AB2 (X₁ = S, G, D, Y, OR family A; X₂ = S, T, OR A;consensus- X₃ = P OR L) IMGT) C7 RASQSISSYLN 79 AASSLQS 82 QQSYSXPLT 84(AB1/AB2 (X = S OR T) consensus- Kabat + Chothia) C8 RASQSISSYLN 79AASSLQS 82 QQSYX₁X₂PX₃T 85 (AB1/AB2 (X₁ = S, G, D, Y, OR familyA; X₂ = S, T, OR A; consensus- X₃ = P OR L) Kabat + Chothia) C9RASQSISSYLN 79 AASSLQS 82 QQSYSXPLT 84 (AB1/AB2 (X = S OR T) consensus-Kabat + IMGT) C10 RASQSISSYLN 79 AASSLQS 82 QQSYX₁X₂PX₃T 85 (AB1/AB2(X₁ = S, G, D, Y, OR family A; X₂ = S, T, OR A; consensus- X₃ = P OR L)Kabat + IMGT) C11 SQSISSY 80 AAS 83 QQSYSXPLT 84 (AB1/AB2 (X = S or T)consensus- Chothia + IMGT) C12 SQSISSY 80 AAS 83 QQSYX₁X₂PX₃T 85(AB1/AB2 (X₁ = S, G, D, Y, OR family A; X₂ = S, T, OR A; consensus-X₃ = P OR L) Chothia + IMGT)

TABLE 11A-2 AB1/AB2 Family Heavy Chain CDR Consensus sequences SEQ IDSEQ ID SEQ ID Binder CDR-H1 NO: CDR-H2: NO: CDR-H3 NO: C1 SYAMS 88AISX₁SGGX₂X₃X₄YADS 92 REWWYDDWYLDY 98 (AB1/AB2 VKG consensus-(X₁ = G or E; X₂ = S or Kabat) R; X₃ = T or A; X₄ = Y or A) C2 SYAMS 88AISX₁X₂GX₃X₄X₅X₆YAD 93 REWWYDDWYLDY 98 (AB1/AB2 SVKG family(X₁ = G, E, or A; X₂ = S, consensus- A, H, or E; X₃ = G, D, Kabat)E ,H, R, or A; X₄ = S, R, V, T, Y; X₅ = T, A, E, H, or R; X₆ = Y,A, or S) C3 GFTFSSY 89 SX₁SGGX₂ 94 REWWYDDWYLDY 98 (AB1/AB2(X₁ = G or E; X₂ = S or consensus- R) Chothia) C4 GFTFSSY 89 SX₁X₂GX₃X₄95 REWWYDDWYLDY 98 (AB1/AB2 (X₁ = G, E, or A; X₂ = S, familyA, H, or E; X₃ = G, D, consensus- E ,H, R, or A; X₄ = S, R, Chothia)V, T, Y) C5 GFTFSSYA 90 ISX₁SGGX₂X₃ 96 ARREWWYDDWYL 99 (AB1/AB2(X₁ = G or E; X₂ = S or DY consensus- R; X₃ = T or A) IMGT) C6 GFTFSSYA90 ISX₁X₂GX₃X₄X₅ 97 ARREWWYDDWYL 99 (AB1/AB2 (X₁ = G, E, or A; X₂ = S,DY family A, H, or E; X₃ = G, D, consensus- E ,H, R, or A; X₄ = S, R,IMGT) V, T, Y; X₅ = T, A, E, H, or R) C7 GFTFSSYAMS 91AISX₁SGGX₂X₃X₄YADS 92 REWWYDDWYLDY 98 (AB1/AB2 VKG consensus-(X₁ = G or E; X₂ = S or Kabat + R; X₃ = T or A; X₄ = Y Chothia) or A) C8GFTFSSYAMS 91 AISX₁X₂GX₃X₄X₅X₆YAD 93 REWWYDDWYLDY 98 (AB1/AB2 SVKGfamily (X₁ = G, E, or A; X₂ = S, consensus- A, H, or E; X₃ = G, D,Kabat + E ,H, R, or A; X₄ = S, R, Chothia) V, T, Y; X₅ =T, A, E, H, or R; X₆ = Y, A, or S) C9 GFTFSSYAMS 91 AISX₁SGGX₂X₃X₄YADS92 ARREWWYDDWYL 99 (AB1/AB2 VKG DY consensus- (X₁ = G or E; X₂ = S orKabat + R; X₃ = T or A; X₄ = Y IMGT) orA) C10 GFTFSSYAMS 91AISX₁X₂GX₃X₄X₅X₆YAD 93 ARREWWYDDWYL 99 (AB1/AB2 SVKG DY family(X₁ = G, E, or A; X₂ = S, consensus- A, H, or E; X₃ = G, D, Kabat +E ,H, R, or A; X₄ = S, R, IMGT) V, T, Y; X₅ = T, A, E, H, or R; X₆ = Y,A, or S) C11 GFTFSSYA 90 ISX₁SGGX₂X₃ 96 ARREWWYDDWYL 99 (AB1/AB2(X₁ = G or E, X₂ = S or DY consensus- R; X₃ = T or A) Chothia + IMGT)C12 GFTFSSYA 90 ISX₁X₂GX₃X₄X₅ 97 ARREWWYDDWYL 99 (AB1/AB2(X₁ = G, E, or A; X₂ = S, DY family A, H, or E; X₃ = G, D, consensus-E ,H, R, or A; X₄ = S, R, Chothia + V, T, Y; X₅ = IMGT)T, A, E, H, or R)

TABLE 11B-1 AB3 Family Light Chain CDR Consensus sequences SEQ SEQ SEQID ID ID Binder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: C13 TGTSSDVGGYNY 100DVSNRX₁X₂ 103 SSYTSSSXLYV 110 (AB3/PI-61 VS (X₁ = L or P; X₂ =(X = A or T) consensus- R or S) Kabat) C14 TGTSSDVGGYNY 100 X₁VSNRX₂X₃104 SSYTSSSXLYV 110 (AB3 family VS (X₁ = D or E; X₂ = (X = A or T)consensus- L, P, or A; X₃ =  Kabat) R, S, G, or W) C15 TSSDVGGYNY 101DVS 105 YTSSSXLY 111 (AB3/PI-61 (X = A or T) consensus- Chothia) C16TSSDVGGYNY 101 XVS 106 YTSSSXLY 111 (AB3 family (X = D or E)(X = A or T) consensus- Chothia) C17 SSDVGGYNY 102 DVSNRX₁X₂GVS 107SSYTSSSXLYV 110 (AB3/PI-61 (X₁ =  L OR P; X₂ = (X = A or T) consensus-R OR S) IMGT with expanded CDR-L2) C18 SSDVGGYNY 102 X₁VSNRX₂X₃GVS 108SSYTSSSXLYV 110 (AB3 family (X₁ = D or E; X₂ = (X = A or T) consensus-L, P, or A; X₃ =  IMGT with R, S, G, or W) expanded CDR-L2) C19TGTSSDVGGYNY 100 DVSNRX₁X₂ 103 SSYTSSSXLYV 110 (AB3/PI-61 VS(X₁ = L OR P; X₂ = (X = A or T) consensus- R OR S) Kabat + Chothia) C20TGTSSDVGGYNY 100 X₁VSNRX₂X₃ 104 SSYTSSSXLYV 110 (AB3 family VS(X₁ = D or E; X₂ = (X = A or T) consensus- L, P, or A; X₃ = Kabat + R, S, G, or W) Chothia) C21 TGTSSDVGGYNY 100 DVSNRX₁X₂ 103 SSYTSSSXLYV110 (AB3/PI-61 VS (X₁ = L OR P; X₂ = (X = A or T) consensus- R OR S)Kabat + IMGT) C22 TGTSSDVGGYNY 100 X₁VSNRX₂X₃ 104 SSYTSSSXLYV 110(AB3 family VS (X₁ = D or E; X₂ = (X = A or T) consensus-L, P, or A; X₃ =  Kabat + R, S, G, or W) IMGT) C23 TSSDVGGYNY 101DVSNRX₁X₂GVS 107 SSYTSSSXLYV 110 (AB3/PI-61 (X₁ = L or P; X₂ =(X = A or T) consensus- R or S) Chothia + IMGT with expanded CDR-L2) C24TSSDVGGYNY 101 X₁VSNRX₂X₃GVS 108 SSYTSSSXLYV 110 (AB3 family(X₁ = D or E; X₂ = (X = A or T) consensus- L, P, or A; X₃ =  Chothia +R, S, G, or W) IMGT with expanded CDR-L2) C25 SSDVGGYNY 102 DVS 105SSYTSSSXLYV 110 (AB3/PI-61 (X = A or T) consensus- IMGT) C26 SSDVGGYNY102 X₁VS 109 SSYTSSSXLYV 110 (AB3 family (X₁ = D or E) (X = A or T)consensus- IMGT) C27 TSSDVGGYNY 101 DVS 105 SSYTSSSXLYV 110 (AB3/PI-61(X = A or T) consensus- Chothia + IMGT) C28 TSSDVGGYNY 101 X₁VS 109SSYTSSSXLYV 110 (AB3 family (X₁ = D or E) (X = A or T) consensus-Chothia + IMGT)

TABLE 11B-2 AB3 Family Heavy Chain CDR Consensus sequences SEQ SEQ SEQID ID ID Binder CDR-H1 NO: CDR-H2: NO: CDR-H3 NO: C13 SYGMH 112VISYXGSNKYYADSV 116 SGYALHDDYYGLD 122 (AB3/PI-61 KG V consensus-(X = T or D) Kabat) C14 SYGMH 112 VISYX₁X₂X₃X₄KYYAD 117SGYX₁X₂X3X4X₅X₆X₇ 123 (AB3 family SVKG x₈x₉DV consensus-(X₁ = H, K, T, R, D, N, (X₁ = A, N, E; X₂ = L, Kabat)S; X₂ = G,D, or E; X₃ = F, V, or Y; X₃ = H, Q, S, T, F, A, L; X₄=  H,R, or D; X₄ = D, E, G, N or K) or Q; X₅ = D, Q, or F;X₆ = Y or Q; X₇ = Y, K, or D ;X₈ = G or P; X₉ = L, Q, V, or T) C15GFTXSSY (X = 113 SYXGSN 118 SGYALHDDYYGLD 122 (AB3/PI-61 V or F)(X = T or D) V consensus- Chothia) C16 GFTXSSY (X = 113 SYX₁X₂X₃X₄KG 119SGYX₁X₂X₃X₄X₅X₆X₇ 123 (AB3 family V or F) (X₁ = H, K, T, R, D, N, x₈x₉DVconsensus- S; X₂ = G,D, or E; X₃ = (X₁ = A, N, E; X₂ = L, Chothia)S, T, F, A, L; X₄ = H, F, V, or Y; X₃ = H, Q, N or K)R, or D; X₄ = D, E, G, or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y,K, or D; X₈ = G or P; X₉ = L, Q, V, or T) C17 GFTXSSYG (X = 114ISYXGSNK (X = T or 120 GGSGYALHDDYYG 124 (AB3/PI-61 V or F) D) LDVconsensus- IMGT) C18 GFTXSSYG (X = 114 ISYX₁X₂X₃X₄K 121 GGSGYX₁X₂X₃X₄X₅X125 (AB3 family V or F) (X₁ = H, K, T, R, D, N, ₆x₇x₈x₉DV consensus-S; X₂ = G, D, or E; X₃ = (X₁ = A, N, E; X₂ = L, IMGT)S, T, F, A, L; X₄ = H, F, V, or Y; X₃ = H, Q, N or K)R, or D; X₄ = D, E, G, or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y,K, or D; X₈ = G or P; X₉ = L, Q, V, or T) C19 GFTXSSYGM 115VISYXGSNKYYADSV 116 SGYALHDDYYGLD 122 (AB3/PI-61 H (X = V or  KG Vconsensus- F) (X = T or D) Kabat + Chothia) C20 GFTXSSYGM 115VISYX₁X₂X₃X₄KYYAD 117 SGYX₁X₂X₃X₄X₅X₆X₇ 123 (AB3 family H (X = V or SVKG x₈x₉DV consensus- F) (X₁ = H, K, T, R, D, N, (X₁ = A, N, E; X₂ = L,Kabat + S; X₂ = G, D, or E; X₃ = F, V, or Y; X₃ = H, Q, Chothia)S, T, F, A, L; X₄ = H, R, or D; X₄ = D, E, G, N or K)or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y, K, or D ;X₈ = G or P;X₉ = L, Q, V, or T) C21 GFTXSSYGM 115 VISYXGSNKYYADSV 116 GGSGYALHDDYYG124 (AB3/PI-61 H (X = V or  KG LDV consensus- F) (X = T or D) Kabat +IMGT) C22 GFTXSSYGM 115 VISYX₁X₂X₃X₄KYYAD 117 GGSGYX₁X₂X₃X₄X₅X₆ 125(AB3 family H (X = V or  SVKG X₇X₈X₉DV consensus- F)(X₁ = H, K, T, R, D, N, (X₁ = A, N, E; X₂ = L, Kabat +S; X₂ = G, D, or E; X₃ = F, V, or Y; X₃ = H, Q, IMGT)S, T, F, A, L; X₄ = H, R, or D; X₄ = D, E, G, N or K)or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y, K, or D; X₈ = G or P;X₉ = L, Q, V, or T) C23 GFTXSSYG  114 ISYXGSNK 120 GGSGYALHDDYYG 124(AB3/PI-61 (X = V or F) (X = T or D) LDV consensus- Chothia + IMGT) C24GFTXSSYG  114 ISYX₁X₂X₃X₄K 121 GGSGYX₁X₂X₃X₄X₅X₆ 125 (AB3 family(X = V or F) (X₁ = H, K, T, R, D, N, X₇X₈X₉DV consensus-S; X₂ = G, D, or E; X₃ = (X₁ = A, N, E; X₂ = L, Chothia +S, T, F, A, L; X₄ = H, F, V, or Y; X₃ = H, Q, IMGT) N or K)R, or D; X₄ = D, E, G, or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y,K, or D; X₈ = G or P; X₉ = L, Q, V, or T) C25 GFTXSSYG  114ISYXGSNK (X = T or 120 GGSGYALHDDYYG 124 (AB3/PI-61 (X = V or F) D) LDVconsensus- IMGT) C26 GFTXSSYG  114 ISYX₁X₂X₃X₄K 121 GGSGYX₁X₂X₃X₄X₅X₆125 (AB3 family (X = V or F) (X₁ = H, K, T, R, D, N, X₇X₈X₉DV consensus-S; X₂ = G, D, or E; X₃ = (X₁ = A, N, E; X₂ = L, IMGT)S, T, F, A, L; X₄ = H, F, V, or Y; X₃ = H, Q, N or K)R, or D; X₄ = D, E, G, or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y,K, or D; X₈ = G or P; X₉ = L, Q, V, or T) C27 GFTXSSYG  114 ISYXGSNK 120GGSGYALHDDYYG 124 (AB3/PI-61 (X = V or F) (X = T or D) LDV consensus-Chothia + IMGT) C28 GFTXSSYG  114 ISYX₁X₂X₃X₄K 121 GGSGYX₁X₂X₃X₄X₅X₆ 125(AB3 family (X = V or F) (X₁ = H, K, T, R, D, N, X₇X₈X₉DV consensus-S; X₂ = G, D, or E; X₃ = (X₁ = A, N, E; X₂ = L, Chothia +S, T, F, A, L; X₄ = H, F, V, or Y; X₃ = H, Q, IMGT) N or K)R, or D; X₄ = D, E, G, or Q; X₅ = D, Q, or F; X₆ = Y or Q; X₇ = Y,K, or D; X₈ = G or P; X₉ = L, Q, V, or T)

TABLE 11C-1AB1/AB2 family BCMA Binders-Light Chain CDR sequences according toKabat numbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2:NO: CDR-L3 NO: AB1 RASQSISSYLN 79 AASSLQS 82 QQSYSSPLT 126 AB2RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 R1F2 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF03 RASQSISSYLN 79 AASSLQS 82 QQSYGSPPT 128 PALF04RASQSISSYLN 79 AASSLQS 82 QQSYDSPLT 129 PALF05 RASQSISSYLN 79 AASSLQS 82QQSYYSPLT 130 PALF06 RASQSISSYLN 79 AASSLQS 82 QQSYYAPLT 131 PALF07RASQSISSYLN 79 AASSLQS 82 QQSYASPLT 132 PALF08 RASQSISSYLN 79 AASSLQS 82QQSYGSPLT 133 PALF09 RASQSISSYLN 79 AASSLQS 82 QQSYDAPLT 134 PALF12RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF13 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF14 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF15RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF16 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF17 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF18RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF19 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF20 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127

TABLE 11C-2 AB1/AB2 family BCMA Binders- Heavy Chain CDR sequences according to Kabat numbering scheme SEQ SEQ SEQ CDR- ID ID IDBinder H1 NO: CDR-H2: NO: CDR-H3 NO: AB1 SYAMS 88 AISGSGGSTYYADS 135REWWYDDWYLDY 98 VKG AB2 SYAMS 88 AISESGGRAAYADS 136 REWWYDDWYLDY 98 VKGR1F2 SYAMS 88 AISGSGGSTYYADS 135 REWWYDDWYLDY 98 VKG PALF03 SYAMS 88AISGSGGSTYYADS 135 REWWYDDWYLDY 98 VKG PALF04 SYAMS 88 AISGSGGSTYYADS135 REWWYDDWYLDY 98 VKG PALF05 SYAMS 88 AISGSGGSTYYADS 135 REWWYDDWYLDY98 VKG PALF06 SYAMS 88 AISGSGGSTYYADS 135 REWWYDDWYLDY 98 VKG PALF07SYAMS 88 AISGSGGSTYYADS 135 REWWYDDWYLDY 98 VKG PALF08 SYAMS 88AISGSGGSTYYADS 135 REWWYDDWYLDY 98 VKG PALF09 SYAMS 88 AISGSGGSTYYADS135 REWWYDDWYLDY 98 VKG PALF12 SYAMS 88 AISGSGGRAAYADS 137 REWWYDDWYLDY98 VKG PALF13 SYAMS 88 AISESGDVEAYADS 138 REWWYDDWYLDY 98 VKG PALF14SYAMS 88 AISEAGETTSYADS 139 REWWYDDWYLDY 98 VKG PALF15 SYAMS 88AISEHGHYTSYADS 140 REWWYDDWYLDY 98 VKG PALF16 SYAMS 88 AISGSGHTAAYADS141 REWWYDDWYLDY 98 VKG PALF17 SYAMS 88 AISGSGRTHAYADS 142 REWWYDDWYLDY98 VKG PALF18 SYAMS 88 AISAEGGVRAYADS 143 REWWYDDWYLDY 98 VKG PALF19SYAMS 88 AISGSGGTTAYADS 144 REWWYDDWYLDY 98 VKG PALF20 SYAMS 88AISGSGATTAYADS 145 REWWYDDWYLDY 98 VKG

TABLE 11D-1 AB1/AB2 family BCMA Binders- Light Chain CDR sequences according to Chothia numbering scheme SEQ  SEQ  SEQ  ID CDR-ID CDR- ID Binder CDR-L1 NO: L2: NO: L3 NO: AB1 SQSISSY 80 AAS 83 SYSSPL146 AB2 SQSISSY 80 AAS 83 SYSTPL 147 R1F2 SQSISSY 80 AAS 83 SYSTPL 147PALF03 SQSISSY 80 AAS 83 SYGSPP 148 PALF04 SQSISSY 80 AAS 83 SYDSPL 149PALF05 SQSISSY 80 AAS 83 SYYSPL 150 PALF06 SQSISSY 80 AAS 83 SYYAPL 151PALF07 SQSISSY 80 AAS 83 SYASPL 152 PALF08 SQSISSY 80 AAS 83 SYGSPL 153PALF09 SQSISSY 80 AAS 83 SYDAPL 154 PALF12 SQSISSY 80 AAS 83 SYSTPL 147PALF13 SQSISSY 80 AAS 83 SYSTPL 147 PALF14 SQSISSY 80 AAS 83 SYSTPL 147PALF15 SQSISSY 80 AAS 83 SYSTPL 147 PALF16 SQSISSY 80 AAS 83 SYSTPL 147PALF17 SQSISSY 80 AAS 83 SYSTPL 147 PALF18 SQSISSY 80 AAS 83 SYSTPL 147PALF19 SQSISSY 80 AAS 83 SYSTPL 147 PALF20 SQSISSY 80 AAS 83 SYSTPL 147

TABLE 11D-2AB1/AB2 family BCMA Binders-Heavy Chain CDR sequences according toChothia numbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-H1 NO: CDR-H2:NO: CDR-H3 NO: AB1 GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98 AB2 GFTFSSY 89SESGGR 156 REWWYDDWYLDY 98 R1F2 GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98PALF03 GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98 PALF04 GFTFSSY 89 SGSGGS155 REWWYDDWYLDY 98 PALF05 GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98 PALF06GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98 PALF07 GFTFSSY 89 SGSGGS 155REWWYDDWYLDY 98 PALF08 GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98 PALF09GFTFSSY 89 SGSGGS 155 REWWYDDWYLDY 98 PALF12 GFTFSSY 89 SGSGGR 157REWWYDDWYLDY 98 PALF13 GFTFSSY 89 SESGDV 158 REWWYDDWYLDY 98 PALF14GFTFSSY 89 SESGDV 158 REWWYDDWYLDY 98 PALF15 GFTFSSY 89 SEHGHY 159REWWYDDWYLDY 98 PALF16 GFTFSSY 89 SGSGHT 160 REWWYDDWYLDY 98 PALF17GFTFSSY 89 SGSGRT 161 REWWYDDWYLDY 98 PALF18 GFTFSSY 89 SAEGGV 162REWWYDDWYLDY 98 PALF19 GFTFSSY 89 SGSGGT 163 REWWYDDWYLDY 98 PALF20GFTFSSY 89 SGSGAT 164 REWWYDDWYLDY 98

TABLE 11E-1AB1/AB2 family BCMA Binders-Light Chain CDR sequences according toIMGT numbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2: NO:CDR-L3 NO: AB1 QSISSY 81 AAS 83 QQSYSSPLT 126 AB2 QSISSY 81 AAS 83QQSYSTPLT 127 R1F2 QSISSY 81 AAS 83 QQSYSTPLT 127 PALF03 QSISSY 81 AAS83 QQSYGSPPT 128 PALF04 QSISSY 81 AAS 83 QQSYDSPLT 129 PALF05 QSISSY 81AAS 83 QQSYYSPLT 130 PALF06 QSISSY 81 AAS 83 QQSYYAPLT 131 PALF07 QSISSY81 AAS 83 QQSYASPLT 132 PALF08 QSISSY 81 AAS 83 QQSYGSPLT 133 PALF09QSISSY 81 AAS 83 QQSYDAPLT 134 PALF12 QSISSY 81 AAS 83 QQSYSTPLT 127PALF13 QSISSY 81 AAS 83 QQSYSTPLT 127 PALF14 QSISSY 81 AAS 83 QQSYSTPLT127 PALF15 QSISSY 81 AAS 83 QQSYSTPLT 127 PALF16 QSISSY 81 AAS 83QQSYSTPLT 127 PALF17 QSISSY 81 AAS 83 QQSYSTPLT 127 PALF18 QSISSY 81 AAS83 QQSYSTPLT 127 PALF19 QSISSY 81 AAS 83 QQSYSTPLT 127 PALF20 QSISSY 81AAS 83 QQSYSTPLT 127

TABLE 11E-2 AB1/AB2 family BCMA Binders- Heavy Chain CDR  sequences according to IMGT numbering scheme SEQ SEQ SEQ ID ID ID BinderCDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB1 GFTFSSYA 90 ISGSGGST 165ARREWWYDDWYL 99 DY AB2 GFTFSSYA 90 ISESGGRA 166 ARREWWYDDWYL 99 DY R1F2GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWYL 99 DY PALF03 GFTFSSYA 90 ISGSGGST165 ARREWWYDDWYL 99 DY PALF04 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWYL 99DY PALF05 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWYL 99 DY PALF06 GFTFSSYA 90ISGSGGST 165 ARREWWYDDWYL 99 DY PALF07 GFTFSSYA 90 ISGSGGST 165ARREWWYDDWYL 99 DY PALF08 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWYL 99 DYPALF09 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWYL 99 DY PALF12 GFTFSSYA 90ISGSGGRA 167 ARREWWYDDWYL 99 DY PALF13 GFTFSSYA 90 ISESGDVE 168ARREWWYDDWYL 99 DY PALF14 GFTFSSYA 90 ISESGDVE 168 ARREWWYDDWYL 99 DYPALF15 GFTFSSYA 90 ISEHGHYT 169 ARREWWYDDWYL 99 DY PALF16 GFTFSSYA 90ISGSGHTA 170 ARREWWYDDWYL 99 DY PALF17 GFTFSSYA 90 ISGSGRTH 171ARREWWYDDWYL 99 DY PALF18 GFTFSSYA 90 ISAEGGVR 172 ARREWWYDDWYL 99 DYPALF19 GFTFSSYA 90 ISGSGGTT 173 ARREWWYDDWYL 99 DY PALF20 GFTFSSYA 90ISGSGATT 174 ARREWWYDDWYL 99 DY

TABLE 11F-1 AB1/AB2 family BCMA Binders- Light Chain CDR sequences according to combination of Kabatand Chothia numbering schemes SEQ SEQ SEQ ID ID ID Binder CDR-L1 NO:CDR-L2: NO: CDR-L3 NO: AB1 RASQSISSYLN 79 AASSLQS 82 QQSYSSPLT 126 AB2RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 R1F2 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF03 RASQSISSYLN 79 AASSLQS 82 QQSYGSPPT 128 PALF04RASQSISSYLN 79 AASSLQS 82 QQSYDSPLT 129 PALF05 RASQSISSYLN 79 AASSLQS 82QQSYYSPLT 130 PALF06 RASQSISSYLN 79 AASSLQS 82 QQSYYAPLT 131 PALF07RASQSISSYLN 79 AASSLQS 82 QQSYASPLT 132 PALF08 RASQSISSYLN 79 AASSLQS 82QQSYGSPLT 133 PALF09 RASQSISSYLN 79 AASSLQS 82 QQSYDAPLT 134 PALF12RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF13 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF14 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF15RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF16 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF17 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF18RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF19 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF20 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127

TABLE 11F-2AB1/AB2 family BCMA Binders-Heavy Chain CDR sequences according to combinationof Kabat and Chothia numbering schemes SEQ ID SEQ ID SEQ ID BinderCDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB1 GFTFSSYAMS 91 AISGSGGSTYYA 135REWWYDDWYLDY 98 DSVKG AB2 GFTFSSYAMS 91 AISESGGRAAYA 136 REWWYDDWYLDY 98DSVKG R1F2 GFTFSSYAMS 91 AISGSGGSTYYA 135 REWWYDDWYLDY 98 DSVKG PALF03GFTFSSYAMS 91 AISGSGGSTYYA 135 REWWYDDWYLDY 98 DSVKG PALF04 GFTFSSYAMS91 AISGSGGSTYYA 135 REWWYDDWYLDY 98 DSVKG PALF05 GFTFSSYAMS 91AISGSGGSTYYA 135 REWWYDDWYLDY 98 DSVKG PALF06 GFTFSSYAMS 91 AISGSGGSTYYA135 REWWYDDWYLDY 98 DSVKG PALF07 GFTFSSYAMS 91 AISGSGGSTYYA 135REWWYDDWYLDY 98 DSVKG PALF08 GFTFSSYAMS 91 AISGSGGSTYYA 135 REWWYDDWYLDY98 DSVKG PALF09 GFTFSSYAMS 91 AISGSGGSTYYA 135 REWWYDDWYLDY 98 DSVKGPALF12 GFTFSSYAMS 91 AISGSGGRAAYA 137 REWWYDDWYLDY 98 DSVKG PALF13GFTFSSYAMS 91 AISESGDVEAYA 138 REWWYDDWYLDY 98 DSVKG PALF14 GFTFSSYAMS91 AISEAGETTSYA 139 REWWYDDWYLDY 98 DSVKG PALF15 GFTFSSYAMS 91AISEHGHYTSYA 140 REWWYDDWYLDY 98 DSVKG PALF16 GFTFSSYAMS 91 AISGSGHTAAYA141 REWWYDDWYLDY 98 DSVKG PALF17 GFTFSSYAMS 91 AISGSGRTHAYA 142REWWYDDWYLDY 98 DSVKG PALF18 GFTFSSYAMS 91 AISAEGGVRAYA 143 REWWYDDWYLDY98 DSVKG PALF19 GFTFSSYAMS 91 AISGSGGTTAYA 144 REWWYDDWYLDY 98 DSVKGPALF20 GFTFSSYAMS 91 AISGSGATTAYA 145 REWWYDDWYLDY 98 DSVKG

TABLE 11G-1AB1/AB2 family BCMA Binders-Light Chain CDR sequences according tocombination of Kabat and IMGT numbering schemes SEQ ID SEQ ID SEQ IDBinder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB1 RASQSISSYLN 79 AASSLQS 82QQSYSSPLT 126 AB2 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 R1F2RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF03 RASQSISSYLN 79 AASSLQS 82QQSYGSPPT 128 PALF04 RASQSISSYLN 79 AASSLQS 82 QQSYDSPLT 129 PALF05RASQSISSYLN 79 AASSLQS 82 QQSYYSPLT 130 PALF06 RASQSISSYLN 79 AASSLQS 82QQSYYAPLT 131 PALF07 RASQSISSYLN 79 AASSLQS 82 QQSYASPLT 132 PALF08RASQSISSYLN 79 AASSLQS 82 QQSYGSPLT 133 PALF09 RASQSISSYLN 79 AASSLQS 82QQSYDAPLT 134 PALF12 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF13RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF14 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF15 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF16RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF17 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127 PALF18 RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF19RASQSISSYLN 79 AASSLQS 82 QQSYSTPLT 127 PALF20 RASQSISSYLN 79 AASSLQS 82QQSYSTPLT 127

TABLE 11G-2 AB1/AB2 family BCMA Binders-Heavy ChainCDR sequences according to combination of Kabatand IMGT numbering schemes SEQ SEQ SEQ ID ID ID Binder CDR-H1 NO:CDR-H2: NO: CDR-H3 NO: AB1 GFTFSSYA 91 AISGSGGSTYY 135 ARREWWYDDWY 99 MSADSVKG LDY AB2 GFTFSSYA 91 AISESGGRAAY 136 ARREWWYDDWY 99 MS ADSVKG LDYR1F2 GFTFSSYA 91 AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF03GFTFSSYA 91 AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF04 GFTFSSYA91 AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF05 GFTFSSYA 91AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF06 GFTFSSYA 91AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF07 GFTFSSYA 91AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF08 GFTFSSYA 91AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF09 GFTFSSYA 91AISGSGGSTYY 135 ARREWWYDDWY 99 MS ADSVKG LDY PALF12 GFTFSSYA 91AISGSGGRAAY 137 ARREWWYDDWY 99 MS ADSVKG LDY PALF13 GFTFSSYA 91AISESGDVEAY 138 ARREWWYDDWY 99 MS ADSVKG LDY PALF14 GFTFSSYA 91AISEAGETTSY 139 ARREWWYDDWY 99 MS ADSVKG LDY PALF15 GFTFSSYA 91AISEHGHYTSY 140 ARREWWYDDWY 99 MS ADSVKG LDY PALF16 GFTFSSYA 91AISGSGHTAAY 141 ARREWWYDDWY 99 MS ADSVKG LDY PALF17 GFTFSSYA 91AISGSGRTHAY 142 ARREWWYDDWY 99 MS ADSVKG LDY PALF18 GFTFSSYA 91AISAEGGVRAY 143 ARREWWYDDWY 99 MS ADSVKG LDY PALF19 GFTFSSYA 91AISGSGGTTAY 144 ARREWWYDDWY 99 MS ADSVKG LDY PALF20 GFTFSSYA 91AISGSGATTAY 145 ARREWWYDDWY 99 MS ADSVKG LDY

TABLE 11H-1 AB1/AB2 family BCMA Binders-Light ChainCDR sequences according to combination ofChothia and IMGT numbering schemes SEQ SEQ SEQ ID ID ID Binder CDR-L1NO: CDR-L2: NO: CDR-L3 NO: AB1 SQSISSY 80 AAS 83 QQSYSSPLT 126 AB2SQSISSY 80 AAS 83 QQSYSTPLT 127 R1F2 SQSISSY 80 AAS 83 QQSYSTPLT 127PALF03 SQSISSY 80 AAS 83 QQSYGSPPT 128 PALF04 SQSISSY 80 AAS 83QQSYDSPLT 129 PALF05 SQSISSY 80 AAS 83 QQSYYSPLT 130 PALF06 SQSISSY 80AAS 83 QQSYYAPLT 131 PALF07 SQSISSY 80 AAS 83 QQSYASPLT 132 PALF08SQSISSY 80 AAS 83 QQSYGSPLT 133 PALF09 SQSISSY 80 AAS 83 QQSYDAPLT 134PALF12 SQSISSY 80 AAS 83 QQSYSTPLT 127 PALF13 SQSISSY 80 AAS 83QQSYSTPLT 127 PALF14 SQSISSY 80 AAS 83 QQSYSTPLT 127 PALF15 SQSISSY 80AAS 83 QQSYSTPLT 127 PALF16 SQSISSY 80 AAS 83 QQSYSTPLT 127 PALF17SQSISSY 80 AAS 83 QQSYSTPLT 127 PALF18 SQSISSY 80 AAS 83 QQSYSTPLT 127PALF19 SQSISSY 80 AAS 83 QQSYSTPLT 127 PALF20 SQSISSY 80 AAS 83QQSYSTPLT 127

TABLE 11H-2 AB1/AB2 family BCMA Binders-Heavy ChainCDR sequences according to combination ofChothia and IMGT numbering schemes SEQ SEQ SEQ ID ID ID Binder CDR-H1NO: CDR-H2: NO: CDR-H3 NO: AB1 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWY 99LDY AB2 GFTFSSYA 90 ISESGGRA 166 ARREWWYDDWY 99 LDY R1F2 GFTFSSYA 90ISGSGGST 165 ARREWWYDDWY 99 LDY PALF03 GFTFSSYA 90 ISGSGGST 165ARREWWYDDWY 99 LDY PALF04 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWY 99 LDYPALF05 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWY 99 LDY PALF06 GFTFSSYA 90ISGSGGST 165 ARREWWYDDWY 99 LDY PALF07 GFTFSSYA 90 ISGSGGST 165ARREWWYDDWY 99 LDY PALF08 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWY 99 LDYPALF09 GFTFSSYA 90 ISGSGGST 165 ARREWWYDDWY 99 LDY PALF12 GFTFSSYA 90ISGSGGRA 167 ARREWWYDDWY 99 LDY PALF13 GFTFSSYA 90 ISESGDVE 168ARREWWYDDWY 99 LDY PALF14 GFTFSSYA 90 ISESGDVE 168 ARREWWYDDWY 99 LDYPALF15 GFTFSSYA 90 ISEHGHYT 169 ARREWWYDDWY 99 LDY PALF16 GFTFSSYA 90ISGSGHTA 170 ARREWWYDDWY 99 LDY PALF17 GFTFSSYA 90 ISGSGRTH 171ARREWWYDDWY 99 LDY PALF18 GFTFSSYA 90 ISAEGGVR 172 ARREWWYDDWY 99 LDYPALF19 GFTFSSYA 90 ISGSGGTT 173 ARREWWYDDWY 99 LDY PALF20 GFTFSSYA 90ISGSGATT 174 ARREWWYDDWY 99 LDY

TABLE 11I-1 AB3 family BCMA Binders-Light Chain CDRsequences according to Kabat numbering scheme SEQ SEQ SEQ ID ID IDBinder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB3 TGTSSDVGGYN 100 DVSNRLR 175SSYTSSSALYV 183 YVS PI-61 TGTSSDVGGYN 100 DVSNRPS 176 SSYTSSSTLYV 184YVS H2/L2-22 TGTSSDVGGYN 100 EVSNRLS 177 SSYTSSSTLYV 184 YVS H2/L2-88TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSALYV 183 YVS H2/L2-36 TGTSSDVGGYN 100EVSNRLR 178 SSYTSSSTLYV 184 YVS H2/L2-34 TGTSSDVGGYN 100 DVSNRPW 179SSYTSSSALYV 183 YVS H2/L2-68 TGTSSDVGGYN 100 DVSNRLS 180 SSYTSSSTLYV 184YVS H2/L2-18 TGTSSDVGGYN 100 DVSNRPW 179 SSYTSSSTLYV 184 YVS H2/L2-47TGTSSDVGGYN 100 DVSNRPW 179 SSYTSSSTLYV 184 YVS H2/L2-20 TGTSSDVGGYN 100DVSNRLR 175 SSYTSSSALYV 183 YVS H2/L2-80 TGTSSDVGGYN 100 DVSNRAW 181SSYTSSSALYV 183 YVS H2/L2-83 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184YVS H3-1 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-2TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-3 TGTSSDVGGYN 100EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-4 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSALYV 183 YVS H3-5 TGTSSDVGGYN 100 EVSNRLS 177 SSYTSSSTLYV 184 YVSH3-6 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSALYV 183 YVS H3-7 TGTSSDVGGYN100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-8 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSTLYV 184 YVS H3-9 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVSH3-10 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-11 TGTSSDVGGYN100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-12 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSTLYV 184 YVS H3-13 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184YVS H3-14 TGTSSDVGGYN 100 EVSNRLS 177 SSYTSSSALYV 183 YVS H3-15TGTSSDVGGYN 100 EVSNRLG 182 SSYTSSSALYV 183 YVS

TABLE 11I-2 AB3 family BCMA Binders-Heavy Chain CDRsequences according to Kabat numbering scheme SEQ SEQ SEQ ID ID IDBinder CDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB3 SYGMH 112 VISYTGSNKYYAD 185SGYALHDDYYGLD 122 SVKG V PI-61 SYGMH 112 VISYDGSNKYYAD 186 SGYALHDDYYGLD122 SVKG V H2/L2-22 SYGMH 112 VISYHGSNKYYAD 187 SGYALHDDYYGLD 122 SVKG VH2/L2-88 SYGMH 112 VISYKGSNKYYAD 188 SGYALHDDYYGLD 122 SVKG V H2/L2-36SYGMH 112 VISYKGSNKYYAD 188 SGYALHDDYYGLD 122 SVKG V H2/L2-34 SYGMH 112VISYTGTKKYYAD 189 SGYALHDDYYGLD 122 SVKG V H2/L2-68 SYGMH 112VISYRGFNKYYAD 190 SGYALHDDYYGQD 199 SVKG V H2/L2-18 SYGMH 112VISYKGSHKYYAD 191 SGYALHDDYYGLD 122 SVKG V H2/L2-47 SYGMH 112VISYKGSNKYYAD 188 SGYALHDDYYGLD 122 SVKG V H2/L2-20 SYGMH 112VISYTGSNKYYAD 185 SGYALHDDYYGLD 122 SVKG V H2/L2-80 SYGMH 112VISYTGSNKYYAD 185 SGYALHDDYYGLD 122 SVKG V H2/L2-83 SYGMH 112VISYKGSNKYYAD 188 SGYALHDDYYGLD 122 SVKG V H3-1 SYGMH 112 VISYDDAHKYYAD192 SGYALHDQYKPVD 200 SVKG V H3-2 SYGMH 112 VISYNDLNKYYAD 193SGYALHDFQDPTD 201 SVKG V H3-3 SYGMH 112 VISYSGSNKYYAD 194 SGYALHDQYKPVD200 SVKG V H3-4 SYGMH 112 VISYDDAHKYYAD 192 SGYALHDQYKPVD 200 SVKG VH3-5 SYGMH 112 VISYTGANKYYAD 195 SGYNLHDDYYGLD 202 SVKG V H3-6 SYGMH 112VISYDDAHKYYAD 192 SGYALHDQYKPVD 200 SVKG V H3-7 SYGMH 112 VISYTGSNKYYAD185 SGYEFHEDYYGLD 203 SVKG V H3-8 SYGMH 112 VISYDDAHKYYAD 192SGYALHDQYKPVD 200 SVKG V H3-9 SYGMH 112 VISYDDAHKYYAD 192 SGYALHDQYKPVD200 SVKG V H3-10 SYGMH 112 VISYNDLNKYYAD 193 SGYEFQGDYYGLD 204 SVKG VH3-11 SYGMH 112 VISYNDANKYYAD 196 SGYELRDDYYGLD 205 SVKG V H3-12 SYGMH112 VISYDESNKYYAD 197 SGYEVDQDYYGLD 206 SVKG V H3-13 SYGMH 112VISYDDAHKYYAD 192 SGYALHDQYKPVD 200 SVKG V H3-14 SYGMH 112 VISYDDAHKYYAD192 SGYALHDQYKPVD 200 SVKG V H3-15 SYGMH 112 VISYDDANKYYAD 198SGYAYDGDYYGLD 207 SVKG V

TABLE 11J-1 AB3 family BCMA Binders-Light Chain CDRsequences according to Chothia numbering scheme SEQ SEQ SEQ ID ID IDBinder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB3 TSSDVGGYNY 101 DVS 105YTSSSALY 209 PI-61 TSSDVGGYNY 101 DVS 105 YTSSSTLY 210 H2/L2-22TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H2/L2-88 TSSDVGGYNY 101 EVS 208YTSSSALY 209 H2/L2-36 TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H2/L2-34TSSDVGGYNY 101 DVS 105 YTSSSALY 209 H2/L2-68 TSSDVGGYNY 101 DVS 105YTSSSTLY 210 H2/L2-18 TSSDVGGYNY 101 DVS 105 YTSSSTLY 210 H2/L2-47TSSDVGGYNY 101 DVS 105 YTSSSTLY 210 H2/L2-20 TSSDVGGYNY 101 DVS 105YTSSSALY 209 H2/L2-80 TSSDVGGYNY 101 DVS 105 YTSSSALY 209 H2/L2-83TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H3-1 TSSDVGGYNY 101 EVS 208 YTSSSTLY210 H3-2 TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H3-3 TSSDVGGYNY 101 EVS 208YTSSSTLY 210 H3-4 TSSDVGGYNY 101 EVS 208 YTSSSALY 209 H3-5 TSSDVGGYNY101 EVS 208 YTSSSTLY 210 H3-6 TSSDVGGYNY 101 EVS 208 YTSSSALY 209 H3-7TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H3-8 TSSDVGGYNY 101 EVS 208 YTSSSTLY210 H3-9 TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H3-10 TSSDVGGYNY 101 EVS208 YTSSSTLY 210 H3-11 TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H3-12TSSDVGGYNY 101 EVS 208 YTSSSTLY 210 H3-13 TSSDVGGYNY 101 EVS 208YTSSSTLY 210 H3-14 TSSDVGGYNY 101 EVS 208 YTSSSALY 209 H3-15 TSSDVGGYNY101 EVS 208 YTSSSALY 209

TABLE 11J-2 AB3 family BCMA Binders-Heavy Chain CDRsequences according to Chothia numbering scheme SEQ SEQ SEQ ID ID IDBinder CDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB3 GFTVSSY 211 SYTGSN 213SGYALHDDYYGLD 122 V PI-61 GFTFSSY  89 SYDGSN 214 SGYALHDDYYGLD 122 VH2/L2-22 GFTFSSY  89 SYHGSN 215 SGYALHDDYYGLD 122 V H2/L2-88 GFTFSSY  89SYKGSN 216 SGYALHDDYYGLD 122 V H2/L2-36 GFTFSSY  89 SYKGSN 216SGYALHDDYYGLD 122 V H2/L2-34 GFTFSSY  89 SYTGTK 217 SGYALHDDYYGLD 122 VH2/L2-68 GFTFSSY  89 SYRGFN 218 SGYALHDDYYGQD 199 V H2/L2-18 GFTFSSY  89SYKGSH 219 SGYALHDDYYGLD 122 V H2/L2-47 GFTFSSY  89 SYKGSN 216SGYALHDDYYGLD 122 V H2/L2-20 GFTVSSY 211 SYTGSN 213 SGYALHDDYYGLD 122 VH2/L2-80 GFTFSSY  89 SYTGSN 213 SGYALHDDYYGLD 122 V H2/L2-83 GFTFSSY  89SYKGSN 216 SGYALHDDYYGLD 122 V H3-1 GFTFSSY  89 SYDDAH 220 SGYALHDQYKPVD200 V H3-2 GFTFSSY  89 SYNDLN 221 SGYALHDFQDPTD 201 V H3-3 GFTVSSY 211SYSGSN 222 SGYALHDQYKPVD 200 V H3-4 GFTFSSY  89 SYDDAH 220 SGYALHDQYKPVD200 V H3-5 GFTFSSY  89 SYTGAN 223 SGYNLHDDYYGLD 202 V H3-6 GFTFSSY  89SYDDAH 220 SGYALHDQYKPVD 200 V H3-7 GFTLSSY 212 SYTGSN 213 SGYEFHEDYYGLD203 V H3-8 GFTFSSY  89 SYDDAH 220 SGYALHDQYKPVD 200 V H3-9 GFTFSSY  89SYDDAH 220 SGYALHDQYKPVD 200 V H3-10 GFTFSSY  89 SYNDLN 221SGYEFQGDYYGLD 204 V H3-11 GFTFSSY  89 SYNDAN 224 SGYELRDDYYGLD 205 VH3-12 GFTFSSY  89 SYDESN 225 SGYEVDQDYYGLD 206 V H3-13 GFTFSSY  89SYDDAH 220 SGYALHDQYKPVD 200 V H3-14 GFTFSSY  89 SYDDAH 220SGYALHDQYKPVD 200 V H3-15 GFTVSSY 211 SYDDAN 226 SGYAYDGDYYGLD 207 V

TABLE 11K-1(a) AB3 family BCMA Binders-CDR-L1 andCDR-L3 sequences according to IMGT numberingscheme and CDR-L2 expanded sequences SEQ SEQ SEQ ID ID ID Binder CDR-L1NO: CDR-L2: NO: CDR-L3 NO: AB3 SSDVGGYNY 102 DVSNRLRGVS 227 SSYTSSSALYV183 PI-61 SSDVGGYNY 102 DVSNRPSGVS 228 SSYTSSSTLYV 184 H2/L2-22SSDVGGYNY 102 EVSNRLSGVS 229 SSYTSSSTLYV 184 H2/L2-88 SSDVGGYNY 102EVSNRLRGVS 230 SSYTSSSALYV 183 H2/L2-36 SSDVGGYNY 102 EVSNRLRGVS 230SSYTSSSTLYV 184 H2/L2-34 SSDVGGYNY 102 DVSNRPWGVS 231 SSYTSSSALYV 183H2/L2-68 SSDVGGYNY 102 DVSNRLSGVS 232 SSYTSSSTLYV 184 H2/L2-18 SSDVGGYNY102 DVSNRPWGVS 231 SSYTSSSTLYV 184 H2/L2-47 SSDVGGYNY 102 DVSNRPWGVS 231SSYTSSSTLYV 184 H2/L2-20 SSDVGGYNY 102 DVSNRLRGVS 227 SSYTSSSALYV 183H2/L2-80 SSDVGGYNY 102 DVSNRAWGVS 233 SSYTSSSALYV 183 H2/L2-83 SSDVGGYNY102 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-1 SSDVGGYNY 102 EVSNRLRGVS 230SSYTSSSTLYV 184 H3-2 SSDVGGYNY 102 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-3SSDVGGYNY 102 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-4 SSDVGGYNY 102EVSNRLRGVS 230 SSYTSSSALYV 183 H3-5 SSDVGGYNY 102 EVSNRLSGVS 229SSYTSSSTLYV 184 H3-6 SSDVGGYNY 102 EVSNRLRGVS 230 SSYTSSSALYV 183 H3-7SSDVGGYNY 102 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-8 SSDVGGYNY 102EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-9 SSDVGGYNY 102 EVSNRLRGVS 230SSYTSSSTLYV 184 H3-10 SSDVGGYNY 102 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-11SSDVGGYNY 102 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-12 SSDVGGYNY 102EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-13 SSDVGGYNY 102 EVSNRLRGVS 230SSYTSSSTLYV 184 H3-14 SSDVGGYNY 102 EVSNRLSGVS 229 SSYTSSSALYV 183 H3-15SSDVGGYNY 102 EVSNRLGGVS 234 SSYTSSSALYV 183

TABLE 11K-1(b) AB3 family BCMA Binders-Light Chain CDRsequences according to IMGT numbering scheme SEQ SEQ SEQ ID ID ID BinderCDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB3 SSDVGGYNY 102 DVS 105 SSYTSSSALYV183 PI-61 SSDVGGYNY 102 DVS 105 SSYTSSSTLYV 184 H2/L2-22 SSDVGGYNY 102EVS 208 SSYTSSSTLYV 184 H2/L2-88 SSDVGGYNY 102 EVS 208 SSYTSSSALYV 183H2/L2-36 SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H2/L2-34 SSDVGGYNY 102DVS 105 SSYTSSSALYV 183 H2/L2-68 SSDVGGYNY 102 DVS 105 SSYTSSSTLYV 184H2/L2-18 SSDVGGYNY 102 DVS 105 SSYTSSSTLYV 184 H2/L2-47 SSDVGGYNY 102DVS 105 SSYTSSSTLYV 184 H2/L2-20 SSDVGGYNY 102 DVS 105 SSYTSSSALYV 183H2/L2-80 SSDVGGYNY 102 DVS 105 SSYTSSSALYV 183 H2/L2-83 SSDVGGYNY 102EVS 208 SSYTSSSTLYV 184 H3-1 SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-2SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-3 SSDVGGYNY 102 EVS 208SSYTSSSTLYV 184 H3-4 SSDVGGYNY 102 EVS 208 SSYTSSSALYV 183 H3-5SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-6 SSDVGGYNY 102 EVS 208SSYTSSSALYV 183 H3-7 SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-8SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-9 SSDVGGYNY 102 EVS 208SSYTSSSTLYV 184 H3-10 SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-11SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-12 SSDVGGYNY 102 EVS 208SSYTSSSTLYV 184 H3-13 SSDVGGYNY 102 EVS 208 SSYTSSSTLYV 184 H3-14SSDVGGYNY 102 EVS 208 SSYTSSSALYV 183 H3-15 SSDVGGYNY 102 EVS 208SSYTSSSALYV 183

TABLE 11K-2 AB3 family BCMA Binders-Heavy Chain CDRsequences according to IMGT numbering scheme SEQ SEQ SEQ ID ID ID BinderCDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB3 GFTVSSYG 235 ISYTGSNK 238GGSGYALHDDYYG 124 LDV PI-61 GFTFSSYG 236 ISYDGSNK 239 GGSGYALHDDYYG 124LDV H2/L2-22 GFTFSSYG 236 ISYHGSNK 240 GGSGYALHDDYYG 124 LDV H2/L2-88GFTFSSYG 236 ISYKGSNK 241 GGSGYALHDDYYG 124 LDV H2/L2-36 GFTFSSYG 236ISYKGSNK 241 GGSGYALHDDYYG 124 LDV H2/L2-34 GFTFSSYG 236 ISYTGTKK 242GGSGYALHDDYYG 124 LDV H2/L2-68 GFTFSSYG 236 ISYRGFNK 243 GGSGYALHDDYYG252 QDV H2/L2-18 GFTFSSYG 236 ISYKGSHK 244 GGSGYALHDDYYG 124 LDVH2/L2-47 GFTFSSYG 236 ISYKGSNK 241 GGSGYALHDDYYG 124 LDV H2/L2-20GFTVSSYG 235 ISYTGSNK 238 GGSGYALHDDYYG 124 LDV H2/L2-80 GFTFSSYG 236ISYTGSNK 238 GGSGYALHDDYYG 124 LDV H2/L2-83 GFTFSSYG 236 ISYKGSNK 241GGSGYALHDDYYG 124 LDV H3-1 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253VDV H3-2 GFTFSSYG 236 ISYNDLNK 246 GGSGYALHDFQDP 254 TDV H3-3 GFTVSSYG235 ISYSGSNK 247 GGSGYALHDQYKP 253 VDV H3-4 GFTFSSYG 236 ISYDDAHK 245GGSGYALHDQYKP 253 VDV H3-5 GFTFSSYG 236 ISYTGANK 248 GGSGYNLHDDYYG 255LDV H3-6 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253 VDV H3-7 GFTLSSYG237 ISYTGSNK 238 GGSGYEFHEDYYG 256 LDV H3-8 GFTFSSYG 236 ISYDDAHK 245GGSGYALHDQYKP 253 VDV H3-9 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253VDV H3-10 GFTFSSYG 236 ISYNDLNK 246 GGSGYEFQGDYYG 257 LDV H3-11 GFTFSSYG236 ISYNDANK 249 GGSGYELRDDYYG 258 LDV H3-12 GFTFSSYG 236 ISYDESNK 250GGSGYEVDQDYYG 259 LDV H3-13 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253VDV H3-14 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253 VDV H3-15 GFTVSSYG235 ISYDDANK 251 GGSGYAYDGDYYG 260 LDV

TABLE 11L-1 AB3 family BCMA Binders-Light Chain CDRsequences according to combination of Kabatand Chothia numbering schemes SEQ SEQ SEQ ID ID ID Binder CDR-L1 NO:CDR-L2: NO: CDR-L3 NO: AB3 TGTSSDVGGYN 100 DVSNRLR 175 SSYTSSSALYV 183YVS PI-61 TGTSSDVGGYN 100 DVSNRPS 176 SSYTSSSTLYV 184 YVS H2/L2-22TGTSSDVGGYN 100 EVSNRLS 177 SSYTSSSTLYV 184 YVS H2/L2-88 TGTSSDVGGYN 100EVSNRLR 178 SSYTSSSALYV 183 YVS H2/L2-36 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSTLYV 184 YVS H2/L2-34 TGTSSDVGGYN 100 DVSNRPW 179 SSYTSSSALYV 183YVS H2/L2-68 TGTSSDVGGYN 100 DVSNRLS 180 SSYTSSSTLYV 184 YVS H2/L2-18TGTSSDVGGYN 100 DVSNRPW 179 SSYTSSSTLYV 184 YVS H2/L2-47 TGTSSDVGGYN 100DVSNRPW 179 SSYTSSSTLYV 184 YVS H2/L2-20 TGTSSDVGGYN 100 DVSNRLR 175SSYTSSSALYV 183 YVS H2/L2-80 TGTSSDVGGYN 100 DVSNRAW 181 SSYTSSSALYV 183YVS H2/L2-83 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-1TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-2 TGTSSDVGGYN 100EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-3 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSTLYV 184 YVS H3-4 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSALYV 183 YVSH3-5 TGTSSDVGGYN 100 EVSNRLS 177 SSYTSSSTLYV 184 YVS H3-6 TGTSSDVGGYN100 EVSNRLR 178 SSYTSSSALYV 183 YVS H3-7 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSTLYV 184 YVS H3-8 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVSH3-9 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-10 TGTSSDVGGYN100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-11 TGTSSDVGGYN 100 EVSNRLR 178SSYTSSSTLYV 184 YVS H3-12 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184YVS H3-13 TGTSSDVGGYN 100 EVSNRLR 178 SSYTSSSTLYV 184 YVS H3-14TGTSSDVGGYN 100 EVSNRLS 177 SSYTSSSALYV 183 YVS H3-15 TGTSSDVGGYN 100EVSNRLG 182 SSYTSSSALYV 183 YVS

TABLE 11L-2 AB3 family BCMA Binders-Heavy Chain CDRsequences according to combination of Kabatand Chothia numbering schemes SEQ SEQ SEQ ID ID ID Binder CDR-H1 NO:CDR-H2: NO: CDR-H3 NO: AB3 GFTVSSYG 261 VISYTGSNKYY 185 SGYALHDDY 122 MHADSVKG YGLDV PI-61 GFTFSSYG 262 VISYDGSNKYY 186 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-22 GFTFSSYG 262 VISYHGSNKYY 187 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-88 GFTFSSYG 262 VISYKGSNKYY 188 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-36 GFTFSSYG 262 VISYKGSNKYY 188 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-34 GFTFSSYG 262 VISYTGTKKYY 189 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-68 GFTFSSYG 262 VISYRGFNKYY 190 SGYALHDDY 199 MH ADSVKGYGQDV H2/L2-18 GFTFSSYG 262 VISYKGSHKYY 191 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-47 GFTFSSYG 262 VISYKGSNKYY 188 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-20 GFTVSSYG 261 VISYTGSNKYY 185 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-80 GFTFSSYG 262 VISYTGSNKYY 185 SGYALHDDY 122 MH ADSVKGYGLDV H2/L2-83 GFTFSSYG 262 VISYKGSNKYY 188 SGYALHDDY 122 MH ADSVKGYGLDV H3-1 GFTFSSYG 262 VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDVH3-2 GFTFSSYG 262 VISYNDLNKYY 193 SGYALHDFQ 201 MH ADSVKG DPTDV H3-3GFTVSSYG 261 VISYSGSNKYY 194 SGYALHDQY 200 MH ADSVKG KPVDV H3-4 GFTFSSYG262 VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDV H3-5 GFTFSSYG 262VISYTGANKYY 195 SGYNLHDDY 202 MH ADSVKG YGLDV H3-6 GFTFSSYG 262VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDV H3-7 GFTLSSYG 263VISYTGSNKYY 185 SGYEFHEDY 203 MH ADSVKG YGLDV H3-8 GFTFSSYG 262VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDV H3-9 GFTFSSYG 262VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDV H3-10 GFTFSSYG 262VISYNDLNKYY 193 SGYEFQGDY 204 MH ADSVKG YGLDV H3-11 GFTFSSYG 262VISYNDANKYY 196 SGYELRDDY 205 MH ADSVKG YGLDV H3-12 GFTFSSYG 262VISYDESNKYY 197 SGYEVDQDY 206 MH ADSVKG YGLDV H3-13 GFTFSSYG 262VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDV H3-14 GFTFSSYG 262VISYDDAHKYY 192 SGYALHDQY 200 MH ADSVKG KPVDV H3-15 GFTVSSYG 261VISYDDANKYY 198 SGYAYDGDY 207 MH ADSVKG YGLDV

TABLE 11M-1 AB3 family BCMA Binders- Light Chain CDR sequencesaccording to combination of Kabat and IMGT numbering schemes SEQ SEQ SEQID ID ID Binder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB3 TGTSSDVGGYNY 100DVSNRLR 175 SSYTSSSALYV 183 VS PI-61 TGTSSDVGGYNY 100 DVSNRPS 176SSYTSSSTLYV 184 VS H2/L2-22 TGTSSDVGGYNY 100 EVSNRLS 177 SSYTSSSTLYV 184VS H2/L2-88 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSALYV 183 VS H2/L2-36TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSTLYV 184 VS H2/L2-34 TGTSSDVGGYNY100 DVSNRPW 179 SSYTSSSALYV 183 VS H2/L2-68 TGTSSDVGGYNY 100 DVSNRLS 180SSYTSSSTLYV 184 VS H2/L2-18 TGTSSDVGGYNY 100 DVSNRPW 179 SSYTSSSTLYV 184VS H2/L2-47 TGTSSDVGGYNY 100 DVSNRPW 179 SSYTSSSTLYV 184 VS H2/L2-20TGTSSDVGGYNY 100 DVSNRLR 175 SSYTSSSALYV 183 VS H2/L2-80 TGTSSDVGGYNY100 DVSNRAW 181 SSYTSSSALYV 183 VS H2/L2-83 TGTSSDVGGYNY 100 EVSNRLR 178SSYTSSSTLYV 184 VS H3-1 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSTLYV 184 VSH3-2 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSTLYV 184 VS H3-3 TGTSSDVGGYNY100 EVSNRLR 178 SSYTSSSTLYV 184 VS H3-4 TGTSSDVGGYNY 100 EVSNRLR 178SSYTSSSALYV 183 VS H3-5 TGTSSDVGGYNY 100 EVSNRLS 177 SSYTSSSTLYV 184 VSH3-6 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSALYV 183 VS H3-7 TGTSSDVGGYNY100 EVSNRLR 178 SSYTSSSTLYV 184 VS H3-8 TGTSSDVGGYNY 100 EVSNRLR 178SSYTSSSTLYV 184 VS H3-9 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSTLYV 184 VSH3-10 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSTLYV 184 VS H3-11 TGTSSDVGGYNY100 EVSNRLR 178 SSYTSSSTLYV 184 VS H3-12 TGTSSDVGGYNY 100 EVSNRLR 178SSYTSSSTLYV 184 VS H3-13 TGTSSDVGGYNY 100 EVSNRLR 178 SSYTSSSTLYV 184 VSH3-14 TGTSSDVGGYNY 100 EVSNRLS 177 SSYTSSSALYV 183 VS H3-15 TGTSSDVGGYNY100 EVSNRLG 182 SSYTSSSALYV 183 VS

TABLE 11M-2 AB3 family BCMA Binders- Heavy Chain CDR sequencesaccording to combination of Kabat and IMGT numbering schemes SEQ SEQ SEQID ID ID Binder CDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB3 GFTVSSYGMH 261VISYTGSNKYY 185 GGSGYALHDDYYG 124 ADSVKG LDV PI-61 GFTFSSYGMH 262VISYDGSNKYY 186 GGSGYALHDDYYG 124 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYHGSNKYY 187 GGSGYALHDDYYG 124 22 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYKGSNKYY 188 GGSGYALHDDYYG 124 88 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYKGSNKYY 188 GGSGYALHDDYYG 124 36 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYTGTKKYY 189 GGSGYALHDDYYG 124 34 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYRGFNKYY 190 GGSGYALHDDYYG 252 68 ADSVKG QDV H2/L2- GFTFSSYGMH 262VISYKGSHKYY 191 GGSGYALHDDYYG 124 18 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYKGSNKYY 188 GGSGYALHDDYYG 124 47 ADSVKG LDV H2/L2- GFTVSSYGMH 261VISYTGSNKYY 185 GGSGYALHDDYYG 124 20 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYTGSNKYY 185 GGSGYALHDDYYG 124 80 ADSVKG LDV H2/L2- GFTFSSYGMH 262VISYKGSNKYY 188 GGSGYALHDDYYG 124 83 ADSVKG LDV H3-1 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-2 GFTFSSYGMH 262VISYNDLNKYY 193 GGSGYALHDFQDP 254 ADSVKG TDV H3-3 GFTVSSYGMH 261VISYSGSNKYY 194 GGSGYALHDQYKP 253 ADSVKG VDV H3-4 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-5 GFTFSSYGMH 262VISYTGANKYY 195 GGSGYNLHDDYYG 255 ADSVKG LDV H3-6 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-7 GFTLSSYGMH 263VISYTGSNKYY 185 GGSGYEFHEDYYG 256 ADSVKG LDV H3-8 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-9 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-10 GFTFSSYGMH 262VISYNDLNKYY 193 GGSGYEFQGDYYG 257 ADSVKG LDV H3-11 GFTFSSYGMH 262VISYNDANKYY 196 GGSGYELRDDYYG 258 ADSVKG LDV H3-12 GFTFSSYGMH 262VISYDESNKYY 197 GGSGYEVDQDYYG 259 ADSVKG LDV H3-13 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-14 GFTFSSYGMH 262VISYDDAHKYY 192 GGSGYALHDQYKP 253 ADSVKG VDV H3-15 GFTVSSYGMH 261VISYDDANKYY 198 GGSGYAYDGDYYG 260 ADSVKG LDV

TABLE 11N-1(a) AB3 family BCMA Binders- CDR-L1 and CDR-L3sequences according to combination of Chothia andIMGT numbering schemes and CDR-L2 expanded sequences SEQ SEQ SEQ ID IDID Binder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB3 TSSDVGGYNY 101DVSNRLRGVS 227 SSYTSSSALYV 183 PI-61 TSSDVGGYNY 101 DVSNRPSGVS 228SSYTSSSTLYV 184 H2/L2-22 TSSDVGGYNY 101 EVSNRLSGVS 229 SSYTSSSTLYV 184H2/L2-88 TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSALYV 183 H2/L2-36TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSTLYV 184 H2/L2-34 TSSDVGGYNY 101DVSNRPWGVS 231 SSYTSSSALYV 183 H2/L2-68 TSSDVGGYNY 101 DVSNRLSGVS 232SSYTSSSTLYV 184 H2/L2-18 TSSDVGGYNY 101 DVSNRPWGVS 231 SSYTSSSTLYV 184H2/L2-47 TSSDVGGYNY 101 DVSNRPWGVS 231 SSYTSSSTLYV 184 H2/L2-20TSSDVGGYNY 101 DVSNRLRGVS 227 SSYTSSSALYV 183 H2/L2-80 TSSDVGGYNY 101DVSNRAWGVS 233 SSYTSSSALYV 183 H2/L2-83 TSSDVGGYNY 101 EVSNRLRGVS 230SSYTSSSTLYV 184 H3-1 TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-2TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-3 TSSDVGGYNY 101EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-4 TSSDVGGYNY 101 EVSNRLRGVS 230SSYTSSSALYV 183 H3-5 TSSDVGGYNY 101 EVSNRLSGVS 229 SSYTSSSTLYV 184 H3-6TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSALYV 183 H3-7 TSSDVGGYNY 101EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-8 TSSDVGGYNY 101 EVSNRLRGVS 230SSYTSSSTLYV 184 H3-9 TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-10TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-11 TSSDVGGYNY 101EVSNRLRGVS 230 SSYTSSSTLYV 184 H3-12 TSSDVGGYNY 101 EVSNRLRGVS 230SSYTSSSTLYV 184 H3-13 TSSDVGGYNY 101 EVSNRLRGVS 230 SSYTSSSTLYV 184H3-14 TSSDVGGYNY 101 EVSNRLSGVS 229 SSYTSSSALYV 183 H3-15 TSSDVGGYNY 101EVSNRLGGVS 234 SSYTSSSALYV 183

TABLE 11N-1(b) AB3 family BCMA Binders- Light Chain CDR sequencesaccording to combination of Chothia and IMGT numbering schemes SEQ SEQSEQ ID ID ID Binder CDR-L1 NO: CDR-L2: NO: CDR-L3 NO: AB3 TSSDVGGYNY 101DVS 105 SSYTSSSALYV 183 PI-61 TSSDVGGYNY 101 DVS 105 SSYTSSSTLYV 184H2/L2-22 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H2/L2-88 TSSDVGGYNY 101EVS 208 SSYTSSSALYV 183 H2/L2-36 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184H2/L2-34 TSSDVGGYNY 101 DVS 105 SSYTSSSALYV 183 H2/L2-68 TSSDVGGYNY 101DVS 105 SSYTSSSTLYV 184 H2/L2-18 TSSDVGGYNY 101 DVS 105 SSYTSSSTLYV 184H2/L2-47 TSSDVGGYNY 101 DVS 105 SSYTSSSTLYV 184 H2/L2-20 TSSDVGGYNY 101DVS 105 SSYTSSSALYV 183 H2/L2-80 TSSDVGGYNY 101 DVS 105 SSYTSSSALYV 183H2/L2-83 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-1 TSSDVGGYNY 101 EVS208 SSYTSSSTLYV 184 H3-2 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-3TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-4 TSSDVGGYNY 101 EVS 208SSYTSSSALYV 183 H3-5 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-6TSSDVGGYNY 101 EVS 208 SSYTSSSALYV 183 H3-7 TSSDVGGYNY 101 EVS 208SSYTSSSTLYV 184 H3-8 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-9TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-10 TSSDVGGYNY 101 EVS 208SSYTSSSTLYV 184 H3-11 TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-12TSSDVGGYNY 101 EVS 208 SSYTSSSTLYV 184 H3-13 TSSDVGGYNY 101 EVS 208SSYTSSSTLYV 184 H3-14 TSSDVGGYNY 101 EVS 208 SSYTSSSALYV 183 H3-15TSSDVGGYNY 101 EVS 208 SSYTSSSALYV 183

TABLE 11N-2 AB3 family BCMA Binders- Heavy Chain CDR sequencesaccording to combination of Chothia and IMGT numbering schemes SEQ SEQSEQ ID ID ID Binder CDR-H1 NO: CDR-H2: NO: CDR-H3 NO: AB3 GFTVSSYG 235ISYTGSNK 238 GGSGYALHDDYYG 124 LDV PI-61 GFTFSSYG 236 ISYDGSNK 239GGSGYALHDDYYG 124 LDV H2/L2- GFTFSSYG 236 ISYHGSNK 240 GGSGYALHDDYYG 12422 LDV H2/L2- GFTFSSYG 236 ISYKGSNK 241 GGSGYALHDDYYG 124 88 LDV H2/L2-GFTFSSYG 236 ISYKGSNK 241 GGSGYALHDDYYG 124 36 LDV H2/L2- GFTFSSYG 236ISYTGTKK 242 GGSGYALHDDYYG 124 34 LDV H2/L2- GFTFSSYG 236 ISYRGFNK 243GGSGYALHDDYYG 252 68 QDV H2/L2- GFTFSSYG 236 ISYKGSHK 244 GGSGYALHDDYYG124 18 LDV H2/L2- GFTFSSYG 236 ISYKGSNK 241 GGSGYALHDDYYG 124 47 LDVH2/L2- GFTVSSYG 235 ISYTGSNK 238 GGSGYALHDDYYG 124 20 LDV H2/L2-GFTFSSYG 236 ISYTGSNK 238 GGSGYALHDDYYG 124 80 LDV H2/L2- GFTFSSYG 236ISYKGSNK 241 GGSGYALHDDYYG 124 83 LDV H3-1 GFTFSSYG 236 ISYDDAHK 245GGSGYALHDQYKP 253 VDV H3-2 GFTFSSYG 236 ISYNDLNK 246 GGSGYALHDFQDP 254TDV H3-3 GFTVSSYG 235 ISYSGSNK 247 GGSGYALHDQYKP 253 VDV H3-4 GFTFSSYG236 ISYDDAHK 245 GGSGYALHDQYKP 253 VDV H3-5 GFTFSSYG 236 ISYTGANK 248GGSGYNLHDDYYG 255 LDV H3-6 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253VDV H3-7 GFTLSSYG 237 ISYTGSNK 238 GGSGYEFHEDYYG 256 LDV H3-8 GFTFSSYG236 ISYDDAHK 245 GGSGYALHDQYKP 253 VDV H3-9 GFTFSSYG 236 ISYDDAHK 245GGSGYALHDQYKP 253 VDV H3-10 GFTFSSYG 236 ISYNDLNK 246 GGSGYEFQGDYYG 257LDV H3-11 GFTFSSYG 236 ISYNDANK 249 GGSGYELRDDYYG 258 LDV H3-12 GFTFSSYG236 ISYDESNK 250 GGSGYEVDQDYYG 259 LDV H3-13 GFTFSSYG 236 ISYDDAHK 245GGSGYALHDQYKP 253 VDV H3-14 GFTFSSYG 236 ISYDDAHK 245 GGSGYALHDQYKP 253VDV H3-15 GFTVSSYG 235 ISYDDANK 251 GGSGYAYDGDYYG 260 LDV

TABLE 11O-1 BCMA Binders - Light chain variable sequences SEQ ID BinderSequence NO: AB1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ264 SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSSPLTFGQGTKVEIK AB2DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK R1F2DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF03DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 266SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYGSPPTFGQGTKVEIK PALF04DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 267SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDSPLTFGQGTKVEIK PALF05DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 268SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYYSPLTFGQGTKVEIK PALF06DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 269SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYYAPLTFGQGTKVEIK PALF07DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 270SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYASPLTFGQGTKVEIK PALF08DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 271SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYGSPLTFGQGTKVEIK PALF09DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 272SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDAPLTFGQGTKVEIK PALF12DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF13DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF14DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF15DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF16DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF17DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF18DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF19DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK PALF20DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ 265SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIK AB3QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 273NRLRGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL PI-61QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 274NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKV TVL H2/L2-22QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 275NRLSGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H2/L2-88QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 276NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL H2/L2-36QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H2/L2-34QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 278NRPWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVM H2/L2-68QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 279NRLSGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H2/L2-18QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 280NRPWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKV TVL H2/L2-47QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 280NRPWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKV TVL H2/L2-20QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 281NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL H2/L2-80QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS 282NRAWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL H2/L2-83QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-1QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-2QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-3QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-4QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 276NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL H3-5QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 275NRLSGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-6QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 276NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL H3-7QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-8QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-9QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 283NRLRGVSNRFSGSKFGNTASLTISGLQAEDEAYYYCSSYTSSSTLYVFGSGTKVT VL H3-10QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-11QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-12QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-13QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 277NRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVT VL H3-14QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 284NRLSGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL H3-15QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVS 285NRLGGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKV TVL

TABLE 11O-2 BCMA Binders - Heavy chain variable sequences SEQ ID BinderSequence NO: AB1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG286 SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDWYLDYWGQGTLVTVSS AB2EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISE 287SGGRAAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDD WYLDYWGQGTLVTVSSR1F2 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF03 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF04 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF05 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF06 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF07 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF08 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF09 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 286SGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF12 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 288SGGRAAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDD WYLDYWGQGTLVTVSSPALF13 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISE 289SGDVEAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF14 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISE 290AGETTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF15 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISE 291HGHYTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF16 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 292SGHTAAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF17 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 293SGRTHAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF18 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISA 294EGGVRAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDD WYLDYWGQGTLVTVSSPALF19 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 295SGGTTAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSPALF20 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISG 296SGATTAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARREWWYDDW YLDYWGQGTLVTVSSAB3 QVQLVESGGGWVQPGRSLRLSCAASGFTVSSYGMHWVRQAPGKGLEWVAVIS 297YTGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSPI-61 QVQLQESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEVWVAVIS 298YDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-22 QAQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 299YHGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSS H2/L2-88QVQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 300YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-36 QAQLQSSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEVWVAVIS 301YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-34 QVQLQDSEGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 302YTGTKKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-68 QAQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 303YRGFNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGQDVWGQGTLVTVSSH2/L2-18 QAQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 304YKGSHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-47 QVQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 300YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-20 QAQLQSSGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQAPGKGLEWVAVIS 305YTGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-80 QVQLQSSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 306YTGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH2/L2-83 QAQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 307YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDD YYGLDVWGQGTLVTVSSH3-1 QVQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 308YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-2 QAQLQESEGGWVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 309YNDLNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDF QDPTDVWGQGTLVTVSSH3-3 QVQLQSSGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQAPGKGLEWVAVIS 310YSGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-4 QVQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 308YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-5 QVQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 311YTGANKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYNLHDD YYGLDVWGQGTLVTVSSH3-6 QAQLQRSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 312YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-7 QVQLQSSEGGVVQPGRSLRLSCAASGFTLSSYGMHWVRQAPGKGLEWVAVIS 313YTGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYEFHED YYGLDVWGQGTLVTVSSH3-8 QAQLQGSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEVWVAVIS 314YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-9 QVQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 308YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-10 QVQLQSSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEVWVAVIS 315YNDLNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYEFQGD YYGLDVWGQGTLVTVSSH3-11 QVQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 316YNDANKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYELRDD YYGLDVWGQGTLVTVSSH3-12 QAQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 317YDESNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYEVDQ DYYGLDVWGQGTLVTVSSH3-13 QVQLQESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEVWVAVIS 318YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-14 QVQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 308YDDAHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDQ YKPVDVWGQGTLVTVSSH3-15 QVQLQGSGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQAPGKGLEWVAVIS 319YDDANKYYADSVKGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCGGSGYAYDG DYYGLDVWGQGTLVTVSS

TABLE 11P BCMA Binders - scFv sequences SEQ ID Binder Sequence NO:H2/L2-88 QVQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 320YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKVTVL H2/L2-36QAQLQSSGGGVVQPGRSLRLSCAASGFTFSSYGMHWWRQAPGKGLEVWVAVIS 321YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVTVL H2/L2-34QVQLQDSEGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 322YTGTKKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKVTVM H2/L2-68QAQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 323YRGFNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGQDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRLSGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVTVL H2/L2-18QAQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 324YKGSHKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVTVL H2/L2-47QVQLQSSEGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 325YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVTVL H2/L2-20QAQLQSSGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQAPGKGLEWVAVIS 326YTGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKVTVL H2/L2-80QVQLQSSGGGVVQPGRSLRLSCAASGFTFSSYGMHWWRQAPGKGLEWVVAVIS 327YTGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRAWGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSALYVFGSGTKVTVL H2/L2-83QAQLQGSGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIS 328YKGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVSSSGGGGSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRLRGVSNRFSGSKFGNTASLTISGLQAEDEADYYCSSYTSSSTLYVFGSGTKVTVL

Tables 11A-1 to 11B-2 list CDR consensus sequences derived from the CDRsequences of exemplary BCMA binding molecules. The CDR consensussequences include sequences based upon the Kabat CDR sequences of theexemplary BCMA binding molecules, the Chothia CDR sequences of theexemplary BCMA binding molecules, the IMGT CDR sequences of theexemplary BCMA binding molecules, a combination of the Kabat and ChothiaCDR sequences of the exemplary BCMA binding molecules, a combination ofthe Kabat and IMGT CDR sequences of the exemplary BCMA bindingmolecules, and a combination of the Chothia and IMGT CDR sequences ofthe exemplary BCMA binding molecules. The specific CDR sequences of theexemplary BCMA binding molecules are listed in Tables 11C1-11N-2.Exemplary VL and VH sequences are listed in Tables 11O-1 and 11O-2,respectively. Exemplary scFv sequences are listed in Table 11P.

In some embodiments, ABM1 comprises a light chain CDR having an aminoacid sequence of any one of the CDR consensus sequences listed in Table11A-1 or Table 11B-1. In particular embodiments, the present disclosureprovides MBMs comprising an ABM1 that comprises (or alternatively,consists of) one, two, three, or more light chain CDRs selected from thelight chain CDRs described in Table 11A-1 or Table 11B-1.

In some embodiments, ABM1 comprises a heavy chain CDR having an aminoacid sequence of any one of the heavy chain CDRs listed in Table 11A-2or Table 11B-2. In particular embodiments, the present disclosureprovides MBMs comprising an ABM1 comprising (or alternatively,consisting of) one, two, three, or more heavy chain CDRs selected theheavy chain CDRs described in Table 11A-2 or Table 11B-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of C1 as set forth in Tables 11A-1 and11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C2 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C3 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C4 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C5 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C6 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C7 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C8 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C9 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of 010 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of 011 as set forth in Tables 11A-1and 11A-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C12 as set forth in Tables 11A-1and 11A-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of C13 as set forth in Tables 11B-1 and11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C14 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C15 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C16 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C17 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C18 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C19 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C20 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C21 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C22 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C23 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C24 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C25 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C26 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C27 as set forth in Tables 11B-1and 11B-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of C28 as set forth in Tables 11B-1and 11B-2.

In some embodiments, ABM1 comprises a light chain CDR having an aminoacid sequence of any one of the CDRs listed in Table 11C-1, Table 11D-1,Table 11E-1, Table 11F-1, Table 11G-1, Table 11H-1, Table 11I-1, Table11J-1, Table 11K-1(a), Table 11K-1(b), Table 11L-1, Table 11M-1, Table11N-1(a) or Table 11N-1(b). In particular embodiments, ABM 1 compriseslight chain CDRs comprising (or alternatively, consisting of) one, two,three, or more light chain CDRs selected the light chain CDRs describedin Table 11C-1, Table 11D-1, Table 11E-1, Table 11F-1, Table 11G-1,Table 11H-1, Table 11I-1, Table 11J-1, Table 11K-1(a), Table 11K-1(b),Table 11L-1, Table 11M-1, Table 11N-1(a) and Table 11N-1(b).

In some embodiments, ABM1 comprises a heavy chain CDR having an aminoacid sequence of any one of the heavy chain CDRs listed in Table 11C-2,Table 11D-2, Table 11E-2, Table 11F-2, Table 11G-2, Table 11H-2, Table11I-2, Table 11J-2, Table 11K-2, Table 11L-2, Table 11M-2, or Table11N-2. In particular embodiments, ABM1 comprises heavy chain CDRscomprising (or alternatively, consisting of) one, two, three, or moreheavy chain CDRs selected the heavy chain CDRs described in Table 11C-2,Table 11D-2, Table 11E-2, Table 11F-2, Table 11G-2, Table 11H-2, Table11I-2, Table 11J-2, Table 11K-2, Table 11L-2, Table 11M-2, and Table11N-2.

In some embodiments, ABM1 comprises a VL domain having an amino acidsequence of any VL domain described in Table 11O-1. In otherembodiments, ABM1 can include amino acids that have been mutated, yethave at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in theVL domain with the VL domains depicted in the sequences described inTable 11O-1.

In some embodiments, ABM1 comprises a VH domain having an amino acidsequence of any VH domain described in Table 11O-2. In otherembodiments, ABM1 can include amino acids that have been mutated, yethave at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in theVH domain with the VH domains depicted in the sequences described inTable 110O-2.

In other embodiments, ABM1 includes amino acids that have been mutated,yet have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity inthe CDR regions with the CDR sequences described in Table 11. In someembodiments, such ABMs include mutant amino acid sequences where no morethan 1, 2, 3, 4 or 5 amino acids have been mutated in the CDR regionswhen compared with the CDR sequences described in Table 11.

Other ABMs include VH and/or VL domains comprising amino acid sequenceshaving at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity tothe VH and/or VL sequences described in Table 11. In some embodiments,ABM1 includes VH and/or VL domains where no more than 1, 2, 3, 4 or 5amino acids have been mutated when compared with the VH and/or VLdomains depicted in the sequences described in Table 11, while retainingsubstantially the same therapeutic activity.

VH and VL sequences (amino acid sequences and the nucleotide sequencesencoding the amino acid sequences) can be “mixed and matched” to createother BCMA binding ABMs. Such “mixed and matched” BCMA binding ABMs canbe tested using known binding assays (e.g., ELISAs). When chains aremixed and matched, a VH sequence from a particular VH/VL pairing shouldbe replaced with a structurally similar VH sequence. A VL sequence froma particular VH/VL pairing should be replaced with a structurallysimilar VL sequence.

Accordingly, in one embodiment, the present disclosure provides MBMshaving an ABM1 comprising: a heavy chain variable region (VH) comprisingan amino acid sequence selected from any one of the VH sequencesdescribed in Table 11-O2; and a light chain variable region (VL)comprising an amino acid sequence described in Table 11-O1.

In another embodiment, the present disclosure provides MBMs having anABM1 comprising a CDR-H1 as described in Table 11, a CDR-H2 as describedin Table 11, a CDR-H3 as described in Table 11, a CDR-L1 as described inTable 11, a CDR-L2 as described in Table 11, and a CDR-L3 as describedin Table 11.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of AB1 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB1 as set forth in Tables 11D-1and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB1 as set forth in Tables 11E-1and 11E-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB1 as set forth in Tables 11F-1and 11F-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB1 as set forth in Tables 11G-1and 11G-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB1 as set forth in Tables 11H-1and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of AB2 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB2 as set forth in Tables 11D-1and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB2 as set forth in Tables 11E-1and 11E-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB2 as set forth in Tables 11F-1and 11F-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB2 as set forth in Tables 11G-1and 11G-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB2 as set forth in Tables 11H-1and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of R1F2 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of R1F2 as set forth in Tables 11D-1and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of R1F2 as set forth in Tables 11E-1and 11E-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of R1F2 as set forth in Tables 11F-1and 11F-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of R1F2 as set forth in Tables 11G-1and 11G-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of R1F2 as set forth in Tables 11H-1and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF03 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF03 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF03 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF03 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF03 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF03 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF04 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF04 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF04 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF04 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF04 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF04 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF05 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF05 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF05 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF05 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF05 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF05 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF06 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF06 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF06 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF06 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF06 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF06 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 of comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF07 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALFC₈ as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALFC₈ as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALFC₈ as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALFC₈ as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALFC₈ asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALFC₈ asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF09 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF12 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF13 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF13 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF13 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF13 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF13 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF13 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF14 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF14 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF14 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF14 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF14 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF14 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF15 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF16 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF16 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF16 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF16 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF16 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF16 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF17 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF17 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF17 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF17 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF17 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF17 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF18 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF18 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF18 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF18 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF18 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF18 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF19 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of PALF20 as set forth in Tables 11C-1 and11C-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 as set forth in Tables11D-1 and 11D-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 as set forth inTables 11E-1 and 11E-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 as setforth in Tables 11F-1 and 11F-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 asset forth in Tables 11G-1 and 11G-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 asset forth in Tables 11H-1 and 11H-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of AB3 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB3 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB3 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB3 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB3 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of AB3 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of P1-61 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of 61 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of P1-61 as set forth in Tables11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of P1-61 as set forth inTables 11L-1 and 11L-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of P1-61 as setforth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of P1-61 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-22 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-22 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-22 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-22 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-22as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-22 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-88 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-88 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-88 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-88 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-88as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-88 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 of comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-36 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-36 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-36 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-36 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-36as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-36 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 of comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-34 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-34 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-34 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-34 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-34as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-34 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-68 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-68 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-68 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-68 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-68as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-68 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-18 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-18 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-18 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-18 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-18as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-18 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-47 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-47 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-47 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-47 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-47as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-47 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 of comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-20 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-20 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-20 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-20 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-20as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-20 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂/L2-80 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-80 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-80 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-80 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-80as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-80 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H₂L2-83 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-83 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-83 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-83 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H₂/L2-83as set forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences ofH₂/L2-83 as set forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-1 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-1 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-1 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-1 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-1 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-1 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-2 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-2 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-2 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-2 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-2 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-2 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 of comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-3 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-3 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-3 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-3 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-3 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-3 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 of comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-4 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-4 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-4 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-4 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-4 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-4 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-5 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-5 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-5 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-5 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-5 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-5 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-6 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-7 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-8 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-8 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-8 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-8 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-8 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-8 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-9 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-9 as set forth in Tables 11J-1and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-9 as set forth in Tables 11K-1and 11K-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-9 as set forth in Tables 11L-1and 11L-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-9 as set forth in Tables 11M-1and 11M-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-9 as set forth in Tables 11N-1and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-10 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-10 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-10 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-10 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-10 asset forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-10 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-11 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 asset forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-12 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 asset forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-13 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 asset forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-14 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-14 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-14 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-14 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-14 asset forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-14 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences of H3-15 as set forth in Tables 11I-1 and11I-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences of H3-15 as set forth in Tables11J-1 and 11J-2. In some embodiments, ABM1 comprises CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-15 as set forth inTables 11K-1 and 11K-2. In some embodiments, ABM1 comprises CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-15 as setforth in Tables 11L-1 and 11L-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-15 asset forth in Tables 11M-1 and 11M-2. In some embodiments, ABM1 comprisesCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-15 asset forth in Tables 11N-1 and 11N-2.

In some embodiments, ABM1 comprises a light chain variable sequenceand/or heavy chain variable sequence of AB1 as set forth in Table 11O-1and Table 11O-2. In some embodiments, ABM1 comprises a light chainvariable sequence and/or heavy chain variable sequence of AB2 as setforth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of R1F2 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of PALF03 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of PALF04 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of PALF05as set forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of PALF06 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of PALF07 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of PALFC₈ as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of PALF09as set forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of PALF12 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of PALF13 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of PALF14 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of PALF15as set forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of PALF16 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of PALF17 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of PALF18 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of PALF19as set forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of PALF20 as set forth in Table 11O-1 and Table 11O-2.In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of AB3 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of PI-61 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of H3-1 asset forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of H3-2 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of H3-3 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of H3-4 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of H3-5 asset forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of H3-6 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of H3-7 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of H3-8 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of H3-9 asset forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of H3-10 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of H3-11 as set forth in Table 11O-1 and Table11O-2. In some embodiments, ABM1 comprises a light chain variablesequence and/or heavy chain variable sequence of H3-12 as set forth inTable 11O-1 and Table 11O-2. In some embodiments, ABM1 comprises a lightchain variable sequence and/or heavy chain variable sequence of H3-13 asset forth in Table 11O-1 and Table 11O-2. In some embodiments, ABM1comprises a light chain variable sequence and/or heavy chain variablesequence of H3-14 as set forth in Table 11O-1 and Table 11O-2. In someembodiments, ABM1 comprises a light chain variable sequence and/or heavychain variable sequence of H3-15 as set forth in Table 11O-1 and Table11O-2.

In some embodiments, ABM1 comprises a scFv sequence of H₂/L2-88 as setforth in Table 11P. In some embodiments, ABM1 comprises a scFv sequenceof H₂/L2-36 as set forth in Table 11P. In some embodiments, ABM1comprises a scFv sequence of H₂/L2-34 as set forth in Table 11P. In someembodiments, ABM1 comprises a scFv sequence of H₂/L2-68 as set forth inTable 11P. In some embodiments, ABM1 comprises a scFv sequence ofH₂/L2-18 as set forth in Table 11P. In some embodiments, ABM1 comprisesa scFv sequence of H₂/L2-47 as set forth in Table 11P. In someembodiments, ABM1 comprises a scFv sequence of H₂/L2-20 as set forth inTable 11P. In some embodiments, ABM1 comprises a scFv sequence ofH₂/L2-80 as set forth in Table 11P. In some embodiments, ABM1 comprisesa scFv sequence of H₂/L2-83 as set forth in Table 11P.

Given that ABM1 binds BCMA, and that antigen binding specificity isprovided primarily by the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, andCDR-L3 regions, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3sequences can be “mixed and matched”. Such “mixed and matched” BCMAbinding ABMs can be tested using known binding assays (e.g., ELISAs).When VH CDR sequences are mixed and matched, the CDR-H1, CDR-H2 and/orCDR-H3 sequence from a particular VH sequence should be replaced with astructurally similar CDR sequence(s). Likewise, when VL CDR sequencesare mixed and matched, the CDR-L1, CDR-L2 and/or CDR-L3 sequence from aparticular VL sequence should be replaced with a structurally similarCDR sequence(s). It will be readily apparent to the ordinarily skilledartisan that novel VH and VL sequences can be created by substitutingone or more VH and/or VL CDR region sequences with structurally similarsequences from CDR sequences shown herein.

In some embodiments, ABM1 comprises a VL sequence selected from the VLsequences set forth in Table 11O-1 and a VH sequence selected the VHsequences set forth in Table 11O-2. In some embodiments, ABM1 comprisesa CDR-H1 sequence selected from the CDR-H1 sequences set forth in Table11A-2, Table 11B-2, Table 11C-2, Table 11D-2, Table 11E-2, Table 11F-2,Table 11G-2, Table 11H-2, Table 11I-2, Table 11J-2, Table 11K-2, Table11L-2, Table 11M-2, and Table 11N-2; a CDR-H2 sequence selected from theCDR-H2 sequences set forth in Table 11A-2, Table 11B-2, Table 11C-2,Table 11D-2, Table 11E-2, Table 11F-2, Table 11G-2, Table 11H-2, Table11I-2, Table 11J-2, Table 11K-2, Table 11L-2, Table 11M-2, and Table11N-2; a CDR-H3 sequence selected from the CDR-H3 sequences set forth inTable 11A-2, Table 11B-2, Table 11C-2, Table 11D-2, Table 11E-2, Table11F-2, Table 11G-2, Table 11H-2, Table 11I-2, Table 11J-2, Table 11K-2,Table 11L-2, Table 11M-2, and Table 11N-2; a CDR-L1 sequence selectedfrom the CDR-L1 sequences set forth in Table 11A-1, Table 11B-1, Table11C-1, Table 11D-1, Table 11E-1, Table 11F-1, Table 11G-1, Table 11H-1,Table 11I-1, Table 11J-1, Table 11K-1(a), Table 11K-1(b), Table 11L-1,Table 11M-1, Table 11N-1(a), and Table 11N-1(b); a CDR-L2 sequenceselected from the CDR-L2 sequences set forth in Table 11A-1, Table11B-1, Table 11C-1, Table 11D-1, Table 11E-1, Table 11F-1, Table 11G-1,Table 11H-1, Table 11I-1, Table 11J-1, Table 11K-1(a), Table 11K-1(b),Table 11L-1, Table 11M-1, Table 11N-1(a), and Table 11N-1(b); and aCDR-L3 sequence selected from the CDR-L3 sequences set forth in Table11A-1, Table 11B-1, Table 11C-1, Table 11D-1, Table 11E-1, Table 11F-1,Table 11G-1, Table 11H-1, Table 11I-1, Table 11J-1, Table 11K-1(a),Table 11K-1(b), Table 11L-1, Table 11M-1, Table 11N-1(a), and Table11N-1(b).

Additional BCMA ABMs can be generated through the techniques ofgene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling(collectively referred to as “DNA shuffling”). DNA shuffling can beemployed to alter the activities of molecules of the disclosure orfragments thereof (e.g., molecules or fragments thereof with higheraffinities and lower dissociation rates). See, generally, U.S. Pat. Nos.5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten etal., (1997) Curr. Opinion Biotechnol. 8:724-33; Harayama, (1998) TrendsBiotechnol. 16(2):76-82; Hansson et al., (1999) J. Mol. Biol.287:265-76; and Lorenzo and Blasco, (1998) Biotechniques 24(2):308- 313.The BCMA ABMs described herein can be altered by being subjected torandom mutagenesis by error-prone PCR, random nucleotide insertion orother methods prior to recombination.

7.6. TCR ABMs

The MBMs (e.g., TBMs) contain an ABM that specifically binds to acomponent of a TCR complex. The TCR is a disulfide-linkedmembrane-anchored heterodimeric protein normally consisting of thehighly variable alpha (α) and beta (β) chains expressed as part of acomplex with the invariant CD3 chain molecules. T cells expressing thisreceptor are referred to as α:β (or αβ) T cells, though a minority of Tcells express an alternate receptor, formed by variable gamma (γ) anddelta (δ) chains, referred as γδ T cells.

In an embodiment, MBMs contain an ABM that specifically binds to CD3.

7.6.1. CD3 ABMs

The MBMs (e.g., TBMs) can contain an ABM that specifically binds to CD3.The term “CD3” refers to the cluster of differentiation 3 co-receptor(or co-receptor complex, or polypeptide chain of the co-receptorcomplex) of the T cell receptor. The amino acid sequence of thepolypeptide chains of human CD3 are provided in NCBI Accession P04234,P07766 and P09693. CD3 proteins can also include variants. CD3 proteinscan also include fragments. CD3 proteins also include post-translationalmodifications of the CD3 amino acid sequences. Post-translationalmodifications include, but are not limited to, N-and 0-linkedglycosylation.

In some embodiments, a MBM (e.g., TBM) can comprise an ABM which is ananti-CD3 antibody (e.g., as described in US 2016/0355600, WO2014/110601, and WO 2014/145806) or an antigen-binding domain thereof.Exemplary anti-CD3 VH, VL, and scFV sequences that can be used in MBMs(e.g., TBMs) are provided in Table 12A.

TABLE 12A CD3 Binders - Variable domain sequences SEQ Binding ID DomainChain Sequence NO: CD3-1 VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQG329 LEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS VLQIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKR 330WIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQW SSNPFTFGSGTKLEIN CD3-2 VHEVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGL 331EWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA VLQAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLF 332TGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWY SNLWVFGGGTKLTVL CD3-3VH QVQLQQSGAELARPGASVKMSCKASGYTFTSYTMHWVKQRPGQG 333LEWIGYINPSSGYTKYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARWQDYDVYFDYWGQGTTLTVSS VLQIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQQKPGSSPKP 334WIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWS SNPPTFGGGTKLETK CD3-4 VHQVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQG 329LEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS VLQIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKR 335WIYDTSKVASGVPYRFSGSGSGTSYSLTISSMEAEDAATYYCQQWS SNPLTFGSGTKLEIN CD3-5 VHQVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKG 336LEWIGYINPSRGYTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQGTPVTVSS VLDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKR 337WIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWS SNPFTFGQGTKLQIT CD3-6 VHQVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKG 338LEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS VLEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRL 339LIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSN WPPLTFGGGTKVEIK CD3-7 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 340EWVGRIRSKYNNYATYYADSVKDRFISRDDSKNSLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQA 341PRGLIGGTNKRAPWTPARFSGSLLGGKAALIGAQAEDEADYYCALW YSNLWVFGGGTKLTVL CD3-8 VHDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGL 342EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS VLDIQLTQSPAIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKR 343WIYDTSKVASGVPYRFSGSGSGTSYSLISSMEAEDAATYYCQQWS SNPLTFGAGTKLELK CD3-9 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKG 344LEWVARIRSKYNNYATYYADSVKDRFISRDDSKNSLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQA 341PRGLIGGTNKRAPWTPARFSGSLLGGKAALIGAQAEDEADYYCALW YSNLWVFGGGTKLTVL CD3-10VH EVKLLESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGL 345EWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA VLQAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLF 332TGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWY SNLWVFGGGTKLTVL CD3-11VH EVQLVESGGGLVQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKG 346LEWVARIRSKYNNYATYYADSVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSS VLQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQA 347PRGLIGGTKFLAPGTPQRFSGSLLGGKAALTLSGVQPEDEAEYYCV LWYSNRWVFGGGTKLTVL CD3-12VH EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKG 348LEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSS VLQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQA 349PRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVL WYSNRWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKG 350LEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL CD3-13 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQG 351LEWMGYINPSRGYTNYNQKFKDRVTMTTDTSISTAYMELSRLRSDDTAVYYCARYYDDHYCLDYWGQGTLVTVSS VLEIVLTQSPATLSLSPGERATLSCSASSSVSYMNWYQQKPGQAPRLLI 352YDTSKLASGVPAHFRGSGSGTDFTLTISSLEPEDFAVYYCQQWSSN PFTFGQGTKVEIK CD3-14 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 353EWVSRIRSKYNNYATYYADSVKDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARHGNFGNSYVSWFAYWGQGTMVTVSS VLQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQA 354PRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCA LWYSNLWVFGGGTKLTVL CD3-15VH EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKG 355LEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQEKPGQA 356PRGLIGGTNKRAPWTPARFSGSLLGGKAALTITGAQAEDEADYYCA LWYSNLWVFGGGTKLTVL CD3-16VH EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKG 357LEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGQA 358PRGLIGGTNKRAPGVPARFSGSLLGGKAALTLSGAQPEDEAEYYCA LWYSNLWVFGGGTKLTVL CD3-17VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 359EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL CD3-18VH QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKG 336LEWIGYINPSRGYTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQGTPVTVSS VLDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKR 361WIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWS SNPFTFGQGT CD3-19 VHQVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKG 362LEWIGYINPSRGYTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYSLDYWGQGTPVTVSS VLDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKR 361WIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWS SNPFTFGQGT CD3-20 VHEVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNL 363EWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS VLDIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLL 364IYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTL PWTFAGGTKLEIK CD3-21 VHEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGL 365EWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQA 366PRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCA LWYSNLWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGL 367EWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGGGTKLTVL CD3-22 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 359EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 368EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL CD3-23 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 369EWVGRIRSKANNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 370EWVGRIRSKANNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL CD3-24 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 371EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDEYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 372EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDEYVSWFAYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL CD3-25 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 373EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDPYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 374EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDPYVSWFAYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL CD3-26 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 375EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFDYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGL 376EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFDYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL CD3-27 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGL 377EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKS 360PRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCA LWYSNHWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGL 378EWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL CD3-28 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKG 357LEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGQA 358PRGLIGGTNKRAPGVPARFSGSLLGGKAALTLSGAQPEDEAEYYCA LWYSNLWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKG 379LEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPGVPARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLGSHHHHHH CD3-129 VHEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGL 380EWVGRIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAHWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTSSNYANWVQQKPGQA 381PRGLIGGTNKRAPWTPARFSGSLLGGKAALTLSGAQPEDEAEYYCA LWYSNLWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGL 382EWVGRIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAHWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTSSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVL CD3-130 VHEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGL 383EWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTAYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS VLQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQA 366PRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCA LWYSNLWVFGGGTKLTVL scFvEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGL 384EWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTAYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGGGTKLTVL

CDR sequences for a number of CD3 binders as defined by the Kabatnumbering scheme (Kabat et al, 1991, Sequences of Proteins ofImmunological Interest, 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md.), Chothia numbering scheme(Al-Lazikani et al., 1997, J. Mol. Biol 273:927-948), and a combinationof Kabat and Chothia numbering are provided in Tables 12B-12D,respectively.

TABLE 12BCD3 Binders - CDR sequences according to Kabat numbering scheme BindingSEQ ID SEQ ID SEQ ID Domain Chain CDR1 NO: CDR2 NO: CDR3 NO: CD3-1 VHRYTMH 385 YINPSRGYTNYNQK 405 YYDDHYCLDY 429 FKD VL SASSSVSYM 386 DTSKLAS406 QQWSSNPFT 430 N CD3-2 VH TYAMN 387 RIRSKYNNYATYYA 407 HGNFGNSYVS 431DSVKD WFAY VL RSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-3 VHSYTMH 389 YINPSSGYTKYNQK 409 WQDYDVYFDY 433 FKD VL RASSSVSYM 390 ATSNLAS410 QQWSSNPPT 434 H CD3-4 VH RYTMH 385 YINPSRGYTNYNQK 405 YYDDHYCLDY 429FKD VL RASSSVSYM 391 DTSKVAS 411 QQWSSNPLT 435 N CD3-5 VH RYTMH 385YINPSRGYTNYNQK 412 YYDDHYCLDY 429 VKD VL SASSSVSYM 386 DTSKLAS 406QQWSSNPFT 430 N CD3-6 VH GYGMH 392 VIWYDGSKKYYVDS 413 QMGYWHFDL 436 VKGVL RASQSVSSY 393 DASNRAT 414 QQRSNWPPLT 437 LA CD3-7 VH TYAMN 387RIRSKYNNYATYYA 415 VRHGNFGNSYV 438 D SWFAY VL RSSTGAVTT 388 GTNKRAP 408ALWYSNLWV 432 SNYAN CD3-8 VH RYTMH 385 YINPSRGYTNYNQK 405 YYDDHYCLDY 429FKD VL RASSSVSYM 391 DTSKVAS 411 QQWSSNPLT 435 N CD3-9 VH TYAMN 387RIRSKYNNYATYYA 415 VRHGNFGNSYV 438 D SWFAY VL RSSTGAVTT 388 GTNKRAP 408ALWYSNLWV 432 SNYAN CD3-10 VH TYAMN 387 RIRSKYNNYATYYA 407 HGNFGNSYVS431 DSVKD WFAY VL RSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-11VH SYAMN 394 RIRSKYNNYATYYA 416 HGNFGNSYVS 439 DSVKG WWAY VL GSSTGAVTS395 GTKFLAP 417 VLWYSNRWV 440 GNYPN CD3-12 VH KYAMN 396 RIRSKYNNYATYYA407 HGNFGNSYISY 441 DSVKD WAY VL GSSTGAVTS 395 GTKFLAP 417 VLWYSNRWV 440GNYPN CD3-13 VH RYTMH 385 YINPSRGYTNYNQK 405 YYDDHYCLDY 429 FKD VLSASSSVSYM 386 DTSKLAS 406 QQWSSNPFT 430 N CD3-14 VH TYAMN 387RIRSKYNNYATYYA 407 HGNFGNSYVS 431 DSVKD WFAY VL RSSTGAVTT 388 GTNKRAP408 ALWYSNLWV 432 SNYAN CD3-15 VH TYAMN 387 RIRSKYNNYATYYA 407HGNFGNSYVS 431 DSVKD WFAY VL RSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432SNYAN CD3-16 VH TYAMN 387 RIRSKYNNYATYYA 416 HGNFGNSYVS 431 DSVKG WFAYVL GSSTGAVTT 397 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-17 VH TYAMN 387RIRSKYNNYATYYA 416 HGNFGDSYVS 442 DSVKG WFAY VL GSSTGAVTT 397 GTNKRAP408 ALWYSNHWV 443 SNYAN CD3-18 VH RYTMH 385 YINPSRGYTNYNQK 412YYDDHYCLDY 429 VKD VL SASSSVSYM 386 DTSKLAS 406 QQWSSNPFT 430 N CD3-19VH RYTMH 385 YINPSRGYTNYNQK 412 YYDDHYSLDY 444 VKD VL SASSSVSYM 386DTSKLAS 406 QQWSSNPFT 430 N CD3-20 VH GYTMN 398 LINPYKGVSTYNQKF 418SGYYGDSDWYF 445 KD DV VL RASQDIRNY 399 YTSRLH 419 QQGNTLPWT 446 LNCD3-21 VH TYAMN 387 RIRSKYNNYATYYA 407 HGNFGNSYVS 431 DSVKD WFAY VLRSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-22 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-23 VH TYAMN 387 RIRSKANNYATYY 420 HGNFGDSYVS442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-24VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDEYVS 447 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-25 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDPYVS 448 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-26 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 449 ADSVKG WFDYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-27 VH TYAMS 400RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-28 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-29VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-30 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-31 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-32 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-33 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-34VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-35 VH TYAMH 401 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-36 VH TYAMS 400 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-37 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-38 VH TYAMN 387 RIRSKANNYYATY 421 HGNFGNSYVS431 YADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-39VH TYAMN 387 RIRSKANSYATYY 422 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-40 VH TYAMN 387 RIRSKYNNYATAY423 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-41 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-42 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-43 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-44VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-45 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-46 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-47 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-48 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-49VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-50 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-51 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGQSYVS 450 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-52 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-53 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS451 ADSVKG WFDY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-54VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-55 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-56 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-57 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-58 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-59VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-60 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 402 GTNKRAP 408 ALWYSNLWV 432SSNYAN CD3-61 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 403 GTNKRAP 408 ALWYSNLWV 432 SGHYAN CD3-62 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 DTNKRAP 424ALWYSNLWV 432 TSNYAN CD3-63 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNNRAP 425 ALWYSNLWV 432 TSNYAN CD3-64VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAS 426 ALWYSNLWV 432 TSNYAN CD3-65 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTSNKHS 427 ALWYSNLWV 432TSNYAN CD3-66 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-67 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-68 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-69VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-70 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-71 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-72 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-73 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 LLWYSNLWV 452 TSNYAN CD3-74VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-75 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-76 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL RSSTGAVT 388 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-77 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL KSSTGAVT 404 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-78 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-79VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-80 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-81 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-82 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-83 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-84VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-85 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-86 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-87 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-88 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-89VH TYAMN 387 RIRSKANNYATYY 420 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-90 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDSYVS 449 ADSVKG WFDY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-91 VH TYAMS 400 RIRSKANNYATYY 420 HGNFGDSYVS 449 ADSVKG WFDYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-92 VH TYAMN 387RIRSNGGYSTYYA 428 HGNFGNSYVS 431 DSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNLWV 432 TSNYAN CD3-93 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-94VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNLWV 432 TSNYAN CD3-95 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNLWV 432TSNYAN CD3-96 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-97 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-98 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-99VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-100 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-101 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-102 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-103 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-104VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-105 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-106 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-107 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-108 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-109VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-110 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-111 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-112 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-113 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-114VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-115 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-116 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-117 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-118 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-119VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-120 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-121 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-122 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-123 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-124VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-125 VH TYAMN 387 RIRSKYNNYATYY416 HGNFGDSYVS 442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443TSNYAN CD3-126 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAYVL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-127 VH TYAMN 387RIRSKYNNYATYY 416 HGNFGNSYVS 431 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408ALWYSNHWV 443 TSNYAN CD3-128 VH TYAMN 387 RIRSKYNNYATYY 416 HGNFGDSYVS442 ADSVKG WFAY VL GSSTGAVT 397 GTNKRAP 408 ALWYSNHWV 443 TSNYAN CD3-129VH TYAMN 387 RIRSKYNNYATYYA 407 HGNFGNSYVS 453 DSVKD WFAH VL GSSTGAVTS402 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-130 VH TYAMN 387 RIRSKYNNYATYYA407 HGNFGNSYVS 431 DSVKD WFAY VL RSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432SNYAN

TABLE 12C CD3 Binders - CDR sequences according to Chothia numberingscheme Binding SEQ ID SEQ ID SEQ ID Domain Chain CDR1 NO: CDR2 NO: CDR3NO: CD3-1 VH GYTFTRY 454 NPSRGY 467 YYDDHYCLDY 429 VL SSSVSY 455 DTS 468WSSNPF 479 CD3-2 VH GFTFNTY 456 RSKYNN 469 HGNFGNSYVS 431 YA WFAY VLSTGAVTTSNY 457 GTN 470 WYSNLW 480 CD3-3 VH GYTFTSY 458 NPSSGY 471WQDYDVYFDY 433 VL SSSVSY 455 ATS 472 WSSNPP 481 CD3-4 VH GYTFTRY 454NPSRGY 467 YYDDHYCLDY 429 VL SSSVSY 455 DTS 468 WSSNPL 482 CD3-5 VHGYTFTRY 454 NPSRGY 467 YYDDHYCLDY 429 VL SSSVSY 455 DTS 468 WSSNPF 479CD3-6 VH GFKFSGY 459 WYDGSK 473 QMGYWHFDL 436 VL SQSVSSY 460 DAS 474RSNWPPL 483 CD3-7 VH GFTFSTY 461 RSKYNN 475 HGNFGNSYVS 484 YAT WFA VLSTGAVTTSNY 457 GTN 470 WYSNLW 480 CD3-8 VH GYTFTRY 454 NPSRGY 467YYDDHYCLDY 429 VL SSSVSY 455 DTS 468 WSSNPL 482 CD3-9 VH GFTFNTY 456RSKYNN 475 HGNFGNSYVS 484 YAT WFA VL STGAVTTSNY 457 GTN 470 WYSNLW 480CD3-10 VH GFTFNTY 456 RSKYNN 469 HGNFGNSYVS 431 YA WFAY VL STGAVTTSNY457 GTN 470 WYSNLW 480 CD3-11 VH GFTFNSY 462 RSKYNN 469 HGNFGNSYVS 439YA WWAY VL STGAVTSGNY 463 GTK 476 WYSNRW 485 CD3-12 VH GFTFNKY 464RSKYNN 469 HGNFGNSYISY 441 YA WAY VL STGAVTSGNY 463 GTK 476 WYSNRW 485CD3-13 VH GYTFTRY 454 NPSRGY 467 YYDDHYCLDY 429 VL SSSVSY 455 DTS 468WSSNPF 479 CD3-14 VH GFTFSTY 461 RSKYNN 469 HGNFGNSYVS 431 YA WFAY VLSTGAVTTSNY 457 GTN 470 WYSNLW 480 CD3-15 VH GFTFNTY 456 RSKYNN 469HGNFGNSYVS 431 YA WFAY VL STGAVTTSNY 457 GTN 470 WYSNLW 480 CD3-16 VHGFTFNTY 456 RSKYNN 469 HGNFGNSYVS 431 YA WFAY VL STGAVTTSNY 457 GTN 470WYSNLW 480 CD3-17 VH GFTFSTY 461 RSKYNN 469 HGNFGDSYVS 442 YA WFAY VLSTGAVTTSNY 457 GTN 470 WYSNHW 486 CD3-18 VH GYTFTRY 454 NPSRGY 467YYDDHYCLDY 429 VL SSSVSY 455 DTS 468 WSSNPF 479 CD3-19 VH GYTFTRY 454NPSRGY 467 YYDDHYSLDY 444 VL SSSVSY 455 DTS 468 WSSNPF 479 CD3-20 VHGYSFTGY 465 NPYKGV 477 SGYYGDSDWY 445 FDV VL SQDIRNY 466 YTS 478 GNTLPW487 CD3-21 VH GFTFNTY 456 RSKYNN 469 HGNFGNSYVS 431 YA WFAY VLRSSTGAVTTS 388 GTNKRA 408 ALWYSNLWV 432 NYAN P

TABLE 12D CD3 Binders - CDR sequences according to combination of Kabatand Chothia numbering schemes Binding SEQ ID SEQ ID SEQ ID Domain ChainCDR1 NO: CDR2 NO: CDR3 NO: CD3-1 VH GYTFTRYTM 488 YINPSRGYTNYN 405YYDDHYCLDY 429 H QKFKD VL SASSSVSYM 386 DTSKLAS 406 QQWSSNPFT 430 NCD3-2 VH GFTFNTYAM 489 RIRSKYNNYATYY 407 HGNFGNSYV 431 N ADSVKD SWFAY VLRSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-3 VH GYTFTSYTM 490YINPSSGYTKYN 409 WQDYDVYFD 433 H QKFKD Y VL RASSSVSYM 390 ATSNLAS 410QQWSSNPPT 434 H CD3-4 VH GYTFTRYTM 488 YINPSRGYTNYN 405 YYDDHYCLDY 429 HQKFKD VL RASSSVSYM 391 DTSKVAS 411 QQWSSNPLT 435 N CD3-5 VH GYTFTRYTM488 YINPSRGYTNYN 412 YYDDHYCLDY 429 H QKVKD VL SASSSVSYM 386 DTSKLAS 406QQWSSNPFT 430 N CD3-6 VH GFKFSGYGM 491 VIWYDGSKKYYV 413 QMGYWHFDL 436 HDSVKG VL RASQSVSSY 393 DASNRAT 414 QQRSNWPPL 437 LA T CD3-7 VH GFTFSTYAM492 RIRSKYNNYATYY 496 HGNFGNSYV 431 N ADSVK SWFAY VL RSSTGAVTT 388GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-8 VH GYTFTRYTM 488 YINPSRGYTNYN 405YYDDHYCLDY 429 H QKFKD VL RASSSVSYM 391 DTSKVAS 411 QQWSSNPLT 435 NCD3-9 VH GFTFNTYAM 489 RIRSKYNNYATYY 496 HGNFGNSYV 431 N ADSVK SWFAY VLRSSTGAVTT 388 GTNKRAP 408 ALWYSNLWV 432 SNYAN CD3-10 VH GFTFNTYAM 489RIRSKYNNYATYY 407 HGNFGNSYV 431 N ADSVKD SWFAY VL RSSTGAVTT 388 GTNKRAP408 ALWYSNLWV 432 SNYAN CD3-11 VH GFTFNSYAM 493 RIRSKYNNYATYY 416HGNFGNSYV 439 N ADSVKG SWWAY VL GSSTGAVTS 395 GTKFLAP 417 VLWYSNRWV 440GNYPN CD3-12 VH GFTFNKYAM 494 RIRSKYNNYATYY 407 HGNFGNSYIS 441 N ADSVKDYWAY VL GSSTGAVTS 395 GTKFLAP 417 VLWYSNRWV 440 GNYPN CD3-13 VHGYTFTRYTM 488 YINPSRGYTNYN 405 YYDDHYCLDY 429 H QKFKD VL SASSSVSYM 386DTSKLAS 406 QQWSSNPFT 430 N CD3-14 VH GFTFSTYAM 492 RIRSKYNNYATYY 407HGNFGNSYV 431 N ADSVKD SWFAY VL RSSTGAVTT 388 GTNKRAP 408 ALWYSNLWW 432SNYAN CD3-15 VH GFTFNTYAM 489 RIRSKYNNYATYY 407 HGNFGNSYV 431 N ADSVKDSWFAY VL RSSTGAVTT 388 GTNKRAP 408 ALWYSNLWW 432 SNYAN CD3-16 VHGFTFNTYAM 489 RIRSKYNNYATYY 416 HGNFGNSYV 431 N ADSVKG SWFAY VLGSSTGAVTT 397 GTNKRAP 408 ALWYSNLWW 432 SNYAN CD3-17 VH GFTFSTYAM 492RIRSKYNNYATYY 416 HGNFGDSYV 442 N ADSVKG SWFAY VL GSSTGAVTT 397 GTNKRAP408 ALWYSNHWV 443 SNYAN CD3-18 VH GYTFTRYTM 488 YINPSRGYTNYN 412YYDDHYCLDY 429 H QKVKD VL SASSSVSYM 386 DTSKLAS 406 QQWSSNPFT 430 NCD3-19 VH GYTFTRYTM 488 YINPSRGYTNYN 412 YYDDHYSLDY 444 H QKVKD VLSASSSVSYM 386 DTSKLAS 406 QQWSSNPFT 430 N CD3-20 VH GYSFTGYTM 495LINPYKGVSTYNQ 418 SGYYGDSDW 445 N KFKD YFDV VL RASQDIRNYL 399 YTSRLHS497 QQGNTLPWT 446 N

In some embodiments, a MBM (e.g., a TBM) can comprise a CD3 ABM whichcomprises the CDRs of any of CD3-1 to CD3-130 as defined by Kabatnumbering (e.g., as set forth in Table 12B). In other embodiments, a MBM(e.g., a TBM) can comprise a CD3 ABM which comprises the CDRs of any ofCD3-1 to CD3-130 as defined by Chothia numbering (e.g., as set forth inTable 12C). In yet other embodiments, a MBM (e.g., a TBM) can comprise aCD3 ABM which comprises the CDRs of any of CD3-1 to CD3-130 as definedby a combination of Kabat and Chothia numbering (e.g., as set forth inTable 12D).

In some embodiments, a CD3 ABM comprises the CDR sequences of CD3-1. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-2. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-3. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-4. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-5. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-6. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-7. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-8. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-9. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-10. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-11. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-12. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-13. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-14. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-15. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-16. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-17. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-18. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-19. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-20. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-21. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-22. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-23. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-24. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-25. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-26. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-27. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-28. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-29. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-30. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-31. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-32. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-33. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-34. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-35. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-36. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-37. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-38. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-39. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-40. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-41. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-42. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-43. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-44. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-45. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-46. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-47. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-48. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-49. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-50. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-51. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-52. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-53. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-54. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-55. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-56. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-57. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-58. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-59. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-60. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-61. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-62. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-63. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-64. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-65. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-66. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-67. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-68. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-69. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-70. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-71. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-72. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-73. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-74. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-75. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-76. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-77. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-78. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-79. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-80. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-81. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-82. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-83. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-84. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-85. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-86. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-87. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-88. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-89. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-90. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-91. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-92. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-93. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-94. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-95. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-96. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-97. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-98. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-99. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-100. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-101. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-102. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-103. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-104. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-105. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-106. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-107. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-108. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-109. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-110. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-111. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-112. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-113. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-114. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-115. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-116. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-117. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-118. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-119. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-120. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-121. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-122. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-123. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-124. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-125. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-126. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-127. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-128. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-129. Insome embodiments, a CD3 ABM comprises the CDR sequences of CD3-130.

A MBM (e.g., a TBM) can comprise the complete heavy and light variablesequences of any one of CD3-1 to CD3-130. In some embodiments, a MBMcomprises a CD3 ABM which comprises the VH and VL sequences of CD3-1. Insome embodiments, a MBM comprises a CD3 ABM which comprises the VH andVL sequences of CD3-1. In some embodiments, a MBM comprises a CD3 ABMwhich comprises the VH and VL sequences of CD3-2. In some embodiments, aMBM comprises a CD3 ABM which comprises the VH and VL sequences ofCD3-3. In some embodiments, a MBM comprises a CD3 ABM which comprisesthe VH and VL sequences of CD3-4. In some embodiments, a MBM comprises aCD3 ABM which comprises the VH and VL sequences of CD3-5. In someembodiments, a MBM comprises a CD3 ABM which comprises the VH and VLsequences of CD3-6. In some embodiments, a MBM comprises a CD3 ABM whichcomprises the VH and VL sequences of CD3-7. In some embodiments, a MBMcomprises a CD3 ABM which comprises the VH and VL sequences of CD3-8. Insome embodiments, a MBM comprises a CD3 ABM which comprises the VH andVL sequences of CD3-9. In some embodiments, a MBM comprises a CD3 ABMwhich comprises the VH and VL sequences of CD3-10. In some embodiments,a MBM comprises a CD3 ABM which comprises the VH and VL sequences ofCD3-11. In some embodiments, a MBM comprises a CD3 ABM which comprisesthe VH and VL sequences of CD3-12. In some embodiments, a MBM comprisesa CD3 ABM which comprises the VH and VL sequences of CD3-13. In someembodiments, a MBM comprises a CD3 ABM which comprises the VH and VLsequences of CD3-14. In some embodiments, a MBM comprises a CD3 ABMwhich comprises the VH and VL sequences of CD3-15. In some embodiments,a MBM comprises a CD3 ABM which comprises the VH and VL sequences ofCD3-16. In some embodiments, a MBM comprises a CD3 ABM which comprisesthe VH and VL sequences of CD3-17. In some embodiments, a MBM comprisesa CD3 ABM which comprises the VH and VL sequences of CD3-18. In someembodiments, a MBM comprises a CD3 ABM which comprises the VH and VLsequences of CD3-19. In some embodiments, a MBM comprises a CD3 ABMwhich comprises the VH and VL sequences of CD3-20. In some embodiments,a MBM comprises a CD3 ABM which comprises the VH and VL sequences ofCD3-21. In some embodiments, a MBM comprises a CD3 ABM which comprisesthe VH and VL sequences of CD3-22. In some embodiments, a MBM comprisesa CD3 ABM which comprises the VH and VL sequences of CD3-23. In someembodiments, a MBM comprises a CD3 ABM which comprises the VH and VLsequences of CD3-24. In some embodiments, a MBM comprises a CD3 ABMwhich comprises the VH and VL sequences of CD3-25. In some embodiments,a MBM comprises a CD3 ABM which comprises the VH and VL sequences ofCD3-26. In some embodiments, a MBM comprises a CD3 ABM which comprisesthe VH and VL sequences of CD3-27. In some embodiments, a MBM comprisesa CD3 ABM which comprises the VH and VL sequences of CD3-28. In someembodiments, a MBM comprises a CD3 ABM which comprises the VH and VLsequences of CD3-129. In some embodiments, a MBM comprises a CD3 ABMwhich comprises the VH and VL sequences of CD3-130.

In addition to the CDR sets described in Tables 12B-12D (i.e., the setof six CDRs for each of CD3-1 to CD3-130), the present disclosureprovides variant CDR sets. In one embodiment, a set of 6 CDRs can have1, 2, 3, 4 or 5 amino acid changes from a CDR set described in Tables12B-12D, as long as the CD3 ABM is still able to bind to the targetantigen, as measured by at least one of a Biacore, surface plasmonresonance (SPR) and/or BLI (biolayer interferometry, e.g., Octet assay)assay.

In addition to the variable heavy and variable light domains disclosedin Table 12A that form an ABM to CD3, the present disclosure providesvariant VH and VL domains. In one embodiment, the variant VH and VLdomains each can have from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acidchanges from the VH and VL domain set forth in Table 12A, as long as theABM is still able to bind to the target antigen, as measured at leastone of a Biacore, surface plasmon resonance (SPR) and/or BLI (biolayerinterferometry, e.g., Octet assay) assay. In another embodiment, thevariant VH and VL are at least 90, 95, 97, 98 or 99% identical to therespective VH or VL disclosed in Table 12A, as long as the ABM is stillable to bind to the target antigen, as measured by at least one of aBiacore, surface plasmon resonance (SPR) and/or BLI (biolayerinterferometry, e.g., Octet assay) assay.

In some embodiments, a MBM can comprise an ABM which is a CD3 bindingmolecule as described in WO 2020/052692 or an antigen-binding domainthereof. Table AA to Table AJ-2 (collectively “Table A”) list sequencesof CD3 binding molecules that can be included in CD3 binding ABMs.

TABLE AA Consensus Group No. C1 Heavy Chain and LightChain CDR Consensus Sequences CDR Binder Sequence SEQ ID NO: CDR-H1 C1-1GFX₁FX₂KX₃GMX₄ 573 CDR-H1 C1-2 GFX₁FX₂KX₃G 574 CDR-H1 C1-3 KX₃GMX₄ 575CDR-H1 C1-4 GFX₁FX₂KX₃ 576 CDR-H2 C1-5 X₅IYYDSSX₆MYYADTVKG 577 CDR-H2C1-6 YYDSSX₆ 578 CDR-H2 C1-7 IYYDSSX₆M 579 CDR-H3 C1-8 X₅₅X₈X₉DLDFDX₁₀580 CDR-H3 C1-9 AX₇X₅₅X₈X₉DLDFDX₁₀ 581 CDR-H3 C1-10 AALNSEYD 582 CDR-H3C1-11 LNSEYD 583 CDR-L1 C1-12 RX₁₁SQSX₁₂X₁₃X₁₄SX₁₅X₁₆TTYFN 584 CDR-L1C1-13 QSX₁₂X₁₃X₁₄SX₁₅TTY 585 CDR-L1 C1-14 SQSX₁₂X₁₃X₁₄SX₁₅X₁₆TTY 586CDR-L1 C1-15 RX₁₁SQSX₁₂X₁₃X₁₄SX₁₅X₁₆ 587 CDR-L1 C1-16 SQSX₁₂X₁₃X₁₄S 588CDR-L1 C1-17 QSX₁₂X₁₃X₁₄S 589 CDR-L2 C1-18 X₁₇X₁₈SX₁₉X₂₀X₂₁X₂₂ 590CDR-L2 C1-19 X₁₇X₁₈S 591 CDR-L3 C1-20 LQX₂₃X₂₄X₂₅X₂₆PX₂₇T 592 CDR-L3C1-21 X₂₃X₂₄X₂₅X₂₆PX₂₇ 593 CDR-L3 C1-22 LQX₂₃X₂₄X₂₅ 594 CDR-L3 C1-23LQX₂₃X₂₄X₂₅X₂₆PX₂₇ 595 X₁ is T or A; X₂ is S or R; X₃ is N, Y, or Q; X₄is H or S; X₅ is M or L; X₆ is K or R; X₇ is S or K; X₅₅ is F, Y, or S;X₈ is W, Y, S, or T; X₉ is W, Y, S, or T; X₁₀ is H or Y; X₁₁ is S or G;X₁₂ is I or L; X₁₃ is V or G; X₁₄ is R or N; X₁₅ is D, E, or L; X₁₆ isG, N, or E; X₁₇ is R or S; X₁₈ is V or T; X₁₉ is N or T; X₂₀ is R or L;X₂₁ is F or E; X₂₂ is S or Y; X₂₃ is S or Y; X₂₄ is S or A; X₂₅ is H orT; X₂₆ is F or Y; X₂₇ is W or Y

TABLE AB Consensus Group No. C2 Heavy Chain and LightChain CDR Consensus Sequences CDR Binder Sequence SEQ ID NO: CDR-H1 C2-1GFSLTTYNX₂₈H 596 CDR-H1 C2-2 GFSLTTYN 597 CDR-H1 C2-3 TYNX₂₈H 598 CDR-H1C2-4 GFSLTTY 599 CDR-H2 C2-5 RMRYSGDTSX₂₉X₃₀X₃₁ALX₃₂S 600 CDR-H2 C2-6RYSGD 601 CDR-H2 C2-7 MRYSGDT 602 CDR-H3 C2-8 DPMYIPX₃₅YX₃₆YGVMNA 603CDR-H3 C2-9 X₃₃X₃₄DPMYIPX₃₅YX₃₆YGVMNA 604 CDR-L1 C2-10 KX₃₇SQNIX₃₈X₃₉YLN605 CDR-L1 C2-11 SQNIX₃₈X₃₉Y 606 CDR-L1 C2-12 QNIX₃₈X₃₉Y 607 CDR-L2C2-13 NTX₄₀X₄₁LX₄₂AGVP 608 CDR-L2 C2-14 NTX₄₀X₄₁LX₄₂A 609 CDR-L2 C2-15NTX₄₀ 610 CDR-L3 C2-16 LQHRSX₄₃YT 611 CDR-L3 C2-17 HRSX₄₃Y 612 X₂₈ is Vor I; X₂₉ is F or Y; X₃₀ is N or S; X₃₁ is A or S; X₃₂ is T or K; X₃₃ isT or A; X₃₄ is S or R; X₃₅ is N or G; X₃₆ is S or A; X₃₇ is A, T, or S;X₃₈ is N or D; X₃₉ is N or K; X₄₀ is D or N; X₄₁ is H or N; X₄₂ is Q orE; X₄₃ is R, S, or G

TABLE AC Consensus Group No. C3 Heavy Chain and LightChain CDR Consensus Sequences CDR Binder Sequence SEQ ID NO: CDR-H1 C3-1GYTFTSYYIY 613 CDR-H1 C3-2 GYTFTSYY 614 CDR-H1 C3-3 SYYIY 615 CDR-H1C3-4 GYTFTSY 458 CDR-H2 C3-5 YIYPX₄₄X₄₅X₄₆X₄₇IYYSEX₄₈FKG 616 CDR-H2 C3-6YPX₄₄X₄₅X₄₆X₄₇ 617 CDR-H2 C3-7 IYPX₄₄X₄₅X₄₆X₄₇I 618 CDR-H3 C3-8X₄₉RPX₅₀TMMAPLX₅₁X₅₂ 619 CDR-H3 C3-9 PX₅₀TMMAPLX₅₁X₅₂ 620 CDR-L1 C3-10RSSQSLX₅₃YSX₅₄GNTYLH 621 CDR-L1 C3-11 SQSLX₅₃YSX₅₄GNTY 622 CDR-L1 C3-12QSLX₅₃YSX₅₄GNTY 623 CDR-L2 C3-13 RVSNRFS 624 CDR-L2 C3-14 RVS 625 CDR-L3C3-15 FQSTHLPYT 626 CDR-L3 C3-16 STHLPY 627 X₄₄ is G or A; X₄₅ is H orN; X₄₆ is D or G; X₄₇ is A or G; X₄₈ is N or K; X₄₉ is V or A; X₅₀ is Nor V; X₅₁ is A or V; X₅₂ is Y or F; X₅₃ is I or V; X₅₄ is I or H

TABLE AD-1 CD3 Binders- Heavy Chain CDR sequences according to Kabatnumbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-H1 NO: CDR-H2 NO:CDR-H3 NO: NOV292 KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKG NOV123SYYIY 615 YIYPGHDAIYYS 635 PNTMMAPLA 642 ENFKG Y Sp10b SYYIY 615YIYPGHDAIYYS 635 PNTMMAPLA 642 ENFKG Y NOV453 TYNVH 629 RMRYSGDTSF 636DPMYIPNYSY 643 NAALTS GVMNA NOV229 TYNVH 629 RMRYSGDTSF 636 DPMYIPNYSY643 NAALTS GVMNA NOV110 SYYIY 615 YIYPANGGIYYS 637 PVTMMAPLV 644 EKFKG FNOV832 SYYIY 615 YIYPANGGIYYS 637 PVTMMAPLV 644 EKFKG F NOV589 KNGMH 628MIYYDSSRMYY 638 FWWDLDFDY 645 ADTVKG NOV580 TYNIH 630 RMRYSGDTSY 639DPMYIPGYSY 646 SSALKS GVMNA NOV567 KYGMS 631 LIYYDSSKMNY 640 LNSEYD 583ADTVKG NOV221 TYNIH 630 RMRYSGDTSY 639 DPMYIPGYSY 646 SSALKS GVMNACD3_sp11a_bkm1 KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_SP11a_bkm2 KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_sp11a_hz0 KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_SP11A_HZ1 KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_sp11a_sansPTM_ KQGMH 632 MIYYDSSKMYY 634 FWWDLDFDH 641 hz1 ADTVKGCD3_sp11a_sansPTM_ KQGMH 632 MIYYDSSKMYY 634 FWWDLDFDH 641 rat ADTVKGCD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FYYDLDFDH 647 YY ADTVKGCD3_SP11A_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FSSDLDFDH 648 SS ADTVKGCD3_SP11A_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FWSDLDFDH 649 WS ADTVKGCD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FSWDLDFDH 650 SW ADTVKGCD3_SP11A_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FTTDLDFDH 651 TT ADTVKGCD3_SP11A_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FTWDLDFDH 652 TW ADTVKGCD3_SP11A_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FWTDLDFDH 653 WT ADTVKGCD3_SP11A VH3_ KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 VLK_3 ADTVKGCD3_sp11a_VH1_VK2 KNQMH 633 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_SP11A_VH3_VLK1 KNGMH 628 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_SP11A_VH5_VK2 KQGMH 632 MIYYDSSKMYY 634 FWWDLDFDH 641 ADTVKGCD3_sp9aFW1_VL_VH_ TYNVH 629 RMRYSGDTSF 636 DPMYIPNYAY 654 S56G NAALTSGVMNA CD3_SP9AFW4_VL_ TYNVH 629 RMRYSGDTSF 636 DPMYIPNYAY 654 VH_S56GNAALTS GVMNA CD3_sp9aFW1_VLVH TYNVH 629 RMRYSGDTSF 636 DPMYIPNYAY 654NAALTS GVMNA CD3_sp9aFW4_VLVH TYNVH 629 RMRYSGDTSF 636 DPMYIPNYAY 654NAALTS GVMNA CD3_sp9arabtor_VHVL TYNVH 629 RMRYSGDTSF 636 DPMYIPNYAY 654NAALTS GVMNA CD3_sp9arabtor_VLVH TYNVH 629 RMRYSGDTSF 636 DPMYIPNYAY 654NAALTS GVMNA CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FYYDLDFDH 647YY_SANSPTM ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 YYYDLDFDH655 YY_SANSPTM_Y ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634SYYDLDFDH 656 YY_SANSPTM_S ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY634 YYYDLDFDH 655 YY_Y ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634SYYDLDFDH 656 YY_s ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634FSSDLDFDH 648 SS_SANSPTM ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY634 YSSDLDFDH 657 SS_SANSPTM_Y ADTVKG CD3_sp11a_VHVL_SS_ KNGMH 628MIYYDSSKMYY 634 SSSDLDFDH 658 SANSPTM_S ADTVKG CD3_sp11a_VHVL_SS_ KNGMH628 MIYYDSSKMYY 634 YSSDLDFDH 657 Y ADTVKG CD3_sp11a_VHVL_SS_ KNGMH 628MIYYDSSKMYY 634 SSSDLDFDH 658 S ADTVKG CD3_sp11a_VHVL_ KNGMH 628MIYYDSSKMYY 634 FSSDLDFDH 648 SS _SANSPTM ADTVKG CD3_sp11a_VHVL_ KNGMH628 MIYYDSSKMYY 634 YWSDLDFDH 659 WS _SANSPTM_Y ADTVKG CD3_sp11a_VHVL_KNGMH 628 MIYYDSSKMYY 634 SWSDLDFDH 660 WS _SANSPTM_S ADTVKGCD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 YWSDLDFDH 659 WS_Y ADTVKGCD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 SWSDLDFDH 660 WS_S ADTVKGCD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 FWSDLDFDH 649 WS _SANSPTMADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 YSWDLDFDH 661SW_SANSPTM_Y ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634 SSWDLDFDH662 SW_SANSPTM_S ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634YSWDLDFDH 661 SW_Y ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634SSWDLDFDH 662 SW_S ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY 634FSWDLDFDH 650 SW_SANSPTM ADTVKG CD3_sp11a_VHVL_ KNGMH 628 MIYYDSSKMYY634 YTWDLDFDH 663 TW_SANSPTM_Y ADTVKG CD3_sp11a_VHVL_ KNGMH 628MIYYDSSKMYY 634 STWDLDFDH 664 TW_SANSPTM_S ADTVKG CD3_sp11a_VHVL_ KNGMH628 MIYYDSSKMYY 634 YTWDLDFDH 663 TW_Y ADTVKG CD3_sp11a_VHVL_ KNGMH 628MIYYDSSKMYY 634 STWDLDFDH 664 TW_S ADTVKG CD3_sp11a_VHVL_ KNGMH 628MIYYDSSKMYY 634 FTWDLDFDH 652 TW_SANSPTM ADTVKG CD3_sp11a_VHVL_ KNGMH628 MIYYDSSKMYY 634 YTTDLDFDH 665 TT _SANSPTM_Y ADTVKG CD3_sp11a_VHVL_TKNGMH 628 MIYYDSSKMYY 634 STTDLDFDH 666 T_SANSPTM_S ADTVKGCD3_sp11a_VHVL_T KNGMH 628 MIYYDSSKMYY 634 YTTDLDFDH 665 T_Y ADTVKGCD3_sp11a_VHVL_T KNGMH 628 MIYYDSSKMYY 634 STTDLDFDH 666 T_S ADTVKGCD3_sp11a_VHVL_T KNGMH 628 MIYYDSSKMYY 634 FTTDLDFDH 651 T_SANSPTMADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 YWWDLDFDH 667 3_YADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 SWWDLDFDH 668 3_SADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 YWWDLDFDH 667 3_Y_PTMADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 SWWDLDFDH 668 3_S_PTMADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 YSWDLDFDH 661 3_Y_SWADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 SSWDLDFDH 662 3_S_SWADTVKG CD3_SP11AVH3_VL_K KNGMH 628 MIYYDSSKMYY 634 YSWDLDFDH 6613_Y_PTM_SW ADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634 SSWDLDFDH662 3_S_SWPTM ADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634FSWDLDFDH 650 SWPTM ADTVKG CD3_SP11AVH3_VLK_ KNGMH 628 MIYYDSSKMYY 634FSWDLDFDH 650 3_SW ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634YWWDLDFDH 667 Y ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634SWWDLDFDH 668 S ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634YWWDLDFDH 667 Y_PTM ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634SWWDLDFDH 668 S_PTM ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634YSWDLDFDH 661 Y_SW ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634SSWDLDFDH 662 S_SW ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634YSWDLDFDH 661 Y_PTM ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634SSWDLDFDH 662 S_PTM_SW ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY634 FSWDLDFDH 650 SW ADTVKG CD3_sp11a_VH1_VK2_ KNQMH 633 MIYYDSSKMYY 634FSWDLDFDH 650 SW_PTM ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY634 YWWDLDFDH 667 Y ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634SWWDLDFDH 668 S ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634YWWDLDFDH 667 Y_PTM ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634SWWDLDFDH 668 S_PTM ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634YSWDLDFDH 661 Y_SW ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634SSWDLDFDH 662 S_SW ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634YWWDLDFDH 667 Y_PTM ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY 634SSWDLDFDH 662 S_PTM_SW ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628 MIYYDSSKMYY634 FSWDLDFDH 650 PTM_SW ADTVKG CD3_SP11A_VH3_VLK1_ KNGMH 628MIYYDSSKMYY 634 FSWDLDFDH 650 SW ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 YWWDLDFDH 667 Y ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 SWWDLDFDH 668 S ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 YWWDLDFDH 667 Y_PTM ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 SWWDLDFDH 668 S_PTM ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 YSWDLDFDH 661 Y_SW ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 SSWDLDFDH 662 S_SW ADTVKG CD3_SP11A_VH5_VK2_ KQGMH 632MIYYDSSKMYY 634 YSWDLDFDH 661 Y_PTM_SW ADTVKG CD3_SP11A_VH5_VK2_ KQGMH632 MIYYDSSKMYY 634 SSWDLDFDH 662 S_PTM_SW ADTVKG CD3_SP11A_VH5_VK2_KQGMH 632 MIYYDSSKMYY 634 FSWDLDFDH 650 PTM_SW ADTVKG CD3_SP11A_VH5_VK2_KQGMH 632 MIYYDSSKMYY 634 FSWDLDFDH 650 SW ADTVKG

TABLE AD-2 CD3 Binders- Light Chain CDR sequences according to Kabatnumbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2 NO:CDR-L3 NO: NOV292 RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WTNOV123 RSSQSLIYSIGN 670 RVSNR 624 FQSTHLP 626 TYLH FS YT Sp10bRSSQSLIYSIGN 670 RVSNR 624 FQSTHLP 626 TYLH FS YT NOV453 KASQNINNYLN 671NTDHL 677 LQHRSR 681 QA YT NOV229 KASQNINNYLN 671 NTDHL 677 LQHRSR 681QA YT NOV110 RSSQSLVYSHG 672 RVSNR 624 FQSTHLP 626 NTYLH FS YT NOV832RSSQSLVYSHG 672 RVSNR 624 FQSTHLP 626 NTYLH FS YT NOV589 RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 GTTYFN FS WT NOV580 KTSQNIDKYLN 673 NTNNL 678LQHRSSY 682 EA T NOV567 RGSQSIGNSLN 674 STSTL 679 LQYATYP 683 EY YTNOV221 KSSQNIDKYLN 675 NTNNL 678 LQHRSG 684 EA YT CD3_sp11a_bkm1RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11a_bkm2RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_sp11a_hz0RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_HZ1RSSQSLVRSD 669 RVSNR 624 LQSSH 685 GTTYFN FS CD3_sp11a_sansPTM_hz1RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 TTYFN FS WT CD3_sp11a_sansPTM_ratRSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 TTYFN FS WT CD3_sp11a_VHVL_YYRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VHVL_SSRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VHVL_WSRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_SWRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VHVL_TTRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VHVL_TWRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VHVL_WTRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VH3_VLK_3RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 TTYFN FS WT CD3_sp11a_VH1_VK2RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_SP11A_VH3_VLK1RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 TTYFN FS WT CD3_SP11A_VH5_VK2RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WTCD3_sp9aFW1 _VL_VH_S56G KASQNINNYLN 671 NTDHL 677 LQHRSR 681 QA YTCD3_SP9AFW4_VL_VH_S56G KASQNINNYLN 671 NTDHL 677 LQHRSR 681 QA YTCD3_sp9aFW1_VLVH KASQNINNYLN 671 NTDHL 677 LQHRSR 681 QA YTCD3_sp9aFW4_VLVH KASQNINNYLN 671 NTDHL 677 LQHRSR 681 QA YTCD3_sp9arabtor_VHVL KASQNINNYLN 671 NTDHL 677 LQHRSR 681 QA YTCD3_sp9arabtor_VLVH KASQNINNYLN 671 NTDHL 677 LQHRSR 681 QA YTCD3_sp11a_VHVL_YY_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM TTYFNFS WT CD3_sp11a_VHVL_YY_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 NSASPTM_YTTYFN FS WT CD3_sp11 a_VHVL_YY_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680SANSPTM_S TTYFN FS WT CD3_sp11a_VHVL_YY_Y RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_YY_s RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_SS_ RSSQSLVRSEG 676 RVSNR 624LQSSHFP 680 SANSPTM TTYFN FS WT CD3_sp11a_VHVL_SS_ RSSQSLVRSEG 676 RVSNR624 LQSSHFP 680 SANSPTM_Y TTYFN FS WT CD3_sp11a_VHVL_SS_ RSSQSLVRSEG 676RVSNR 624 LQSSHFP 680 SANSPTM_S TTYFN FS WT CD3_sp11a_VHVL_SS_YRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_SS_SRSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_SS_RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM TTYFN FS WTCD3_sp11a_VHVL_WS_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM_Y TTYFNFS WT CD3_sp11a_VHVL_WS_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM_STTYFN FS WT CD3_sp11a_VHVL_ WS _Y RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680GTTYFN FS WT CD3_sp11a_VHVL_ WS _S RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680GTTYFN FS WT CD3_sp11a_VHVL_WS_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680SANSPTM TTYFN FS WT CD3_sp11a_VHVL_SW_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP680 SANSPTM_Y TTYFN FS WT CD3_sp11a_VHVL_SW_ RSSQSLVRSEG 676 RVSNR 624LQSSHFP 680 SANSPTM_S TTYFN FS WT CD3_sp11a_VHVL_SW_Y RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_SW_S RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_SW_ RSSQSLVRSEG 676RVSNR 624 LQSSHFP 680 SANSPTM TTYFN FS WT CD3_sp11a_VHVL_TW_ RSSQSLVRSEG676 RVSNR 624 LQSSHFP 680 SANSPTM_Y TTYFN FS WT CD3_sp11a_VHVL_TW_RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM_S TTYFN FS WTCD3_sp11a_VHVL_TW_Y RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WTCD3_sp11a_VHVL_TW_S RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WTCD3_sp11a_VHVL_TW_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM TTYFNFS WT CD3_sp11a_VHVL_TT_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SANSPTM_YTTYFN FS WT CD3_sp11a_VHVL_TT_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680SANSPTM_S TTYFN FS WT CD3_sp11a_VHVL_TT_Y RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_TT_S RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VHVL_TT_ RSSQSLVRSEG 676 RVSNR 624LQSSHFP 680 SANSPTM TTYFN FS WT CD3_SP11AVH3_VLK_3_Y RSSQSLVRSEG 676RVSNR 624 LQSSHFP 680 TTYFN FS WT CD3_SP11AVH3_VLK_3_S RSSQSLVRSEG 676RVSNR 624 LQSSHFP 680 TTYFN FS WT CD3_SP11AVH3_VLK_3_Y_ RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 PTM GTTYFN FS WT CD3_SP11AVH3_VLK_3_S_ RSSQSLVRSD669 RVSNR 624 LQSSHFP 680 PTM GTTYFN FS WT CD3_SP11AVH3_VLK_3_Y_RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SW TTYFN FS WTCD3_SP11AVH3_VLK_3_S_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SW TTYFN FSWT CD3_SP11AVH3_VLK_3_Y_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 PTM_SWGTTYFN FS WT CD3_SP11AVH3_VLK_3_S_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680SWPTM GTTYFN FS WT CD3_SP11AVH3_VLK_SWPTM RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_SP11AVH3_VLK_3_SW RSSQSLVRSEG 676 RVSNR 624LQSSHFP 680 TTYFN FS WT CD3_sp11a_VH1_VK2_Y RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VH1_VK2_S RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 GTTYFN FS WT CD3_sp11a_VH1_VK2_Y_ RSSQSLVRSEG 676 RVSNR 624LQSSHFP 680 PTM TTYFN FS WT CD3_sp11a_VH1_VK2_S_ RSSQSLVRSEG 676 RVSNR624 LQSSHFP 680 PTM TTYFN FS WT CD3_sp11a_VH1_VK2_Y_ RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 sw GTTYFN FS WT CD3_sp11a_VH1_VK2_S_ RSSQSLVRSD669 RVSNR 624 LQSSHFP 680 SW GTTYFN FS WT CD3_sp11a_VH1_VK2_Y_RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 PTM TTYFN FS WTCD3_sp11a_VH1_VK2_S_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 PTM_SW TTYFNFS WT CD3_sp11a_VH1_VK2_SW RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFNFS WT CD3_sp11a_VH1_VK2_SW_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 PTMTTYFN FS WT CD3_SP11A_VH3_VLK1_Y RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680TTYFN FS WT CD3_SP11A_VH3_VLK1_S RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680TTYFN FS WT CD3_SP11A_VH3_VLK1_Y_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680PTM GTTYFN FS WT CD3_SP11A_VH3_VLK1_S_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP680 PTM GTTYFN FS WT CD3_SP11A_VH3_VLK1_Y_ RSSQSLVRSEG 676 RVSNR 624LQSSHFP 680 SW TTYFN FS WT CD3_SP11A_VH3_VLK1_S_ RSSQSLVRSEG 676 RVSNR624 LQSSHFP 680 SW TTYFN FS WT CD3_SP11A_VH3_VLK1_Y_ RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 PTM GTTYFN FS WT CD3_SP11A_VH3_VLK1_S_ RSSQSLVRSD669 RVSNR 624 LQSSHFP 680 PTM_SW GTTYFN FS WT CD3_SP11A_VH3_VLK1_RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 PTM_SW GTTYFN FS WTCD3_SP11A_VH3_VLK1_ RSSQSLVRSEG 676 RVSNR 624 LQSSHFP 680 SW TTYFN FS WTCD3_SP11A_VH5_VK2_Y RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WTCD3_SP11A_VH5_VK2_S RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 GTTYFN FS WTCD3_SP11A_VH5_VK2_Y_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 PTM GTTYFN FSWT CD3_SP11A_VH5_VK2_S_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 PTM GTTYFNFS WT CD3_SP11A_VH5_VK2_Y_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680 swGTTYFN FS WT CD3_SP11A_VH5_VK2_S_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP 680SW GTTYFN FS WT CD3_SP11A_VH5_VK2_Y_ RSSQSLVRSD 669 RVSNR 624 LQSSHFP680 PTM_SW GTTYFN FS WT CD3_SP11A_VH5_VK2_S_ RSSQSLVRSD 669 RVSNR 624LQSSHFP 680 PTM_SW GTTYFN FS WT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNR624 LQSSHFP 680 PTM_SW GTTYFN FS WT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669RVSNR 624 LQSSHFP 680 SW GTTYFN FS WT

TABLE AE-1 CD3 Binders- Heavy Chain CDR sequences according to Chothianumbering scheme SEQ SEQ ID SEQ ID Binder CDR-H1 ID NO: CDR-H2 NO:CDR-H3 NO: NOV292 GFTFSKN 686 YYDSSK 689 FWWDLDFDH 641 NOV123 GYTFTSY458 YPGHDA 690 PNTMMAPLAY 642 Sp10b GYTFTSY 458 YPGHDA 690 PNTMMAPLAY642 NOV453 GFSLTTY 599 RYSGD 601 DPMYIPNYSYG 643 VMNA NOV229 GFSLTTY 599RYSGD 601 DPMYIPNYSYG 643 VMNA NOV110 GYTFTSY 458 YPANGG 691 PVTMMAPLVF644 NOV832 GYTFTSY 458 YPANGG 691 PVTMMAPLVF 644 NOV589 GFTFSKN 686YYDSSR 692 FWWDLDFDY 645 NOV580 GFSLTTY 599 RYSGD 601 DPMYIPGYSYG 646VMNA NOV567 GFAFRKY 687 YYDSSK 689 LNSEYD 583 NOV221 GFSLTTY 599 RYSGD601 DPMYIPGYSYG 646 VMNA CD3_sp11a_bkm1 GFTFSKN 686 YYDSSK 689 FWWDLDFDH641 CD3_SP11a_bkm2 GFTFSKN 686 YYDSSK 689 FWWDLDFDH 641 CD3_sp11a_hz0GFTFSKN 686 YYDSSK 689 FWWDLDFDH 641 CD3_SP11A_HZ1 GFTFSKN 686 YYDSSK689 FWWDLDFDH 641 CD3_sp11a_sansPTM_hz1 GFTFSKQ 688 YYDSSK 689 FWWDLDFDH641 CD3_sp11a_sansPTM_rat GFTFSKQ 688 YYDSSK 689 FWWDLDFDH 641CD3_sp11a_VHVL_YY GFTFSKN 686 YYDSSK 689 FYYDLDFDH 647 CD3_SP11A_VHVL_SSGFTFSKN 686 YYDSSK 689 FSSDLDFDH 648 CD3_SP11A_VHVL_WS GFTFSKN 686YYDSSK 689 FWSDLDFDH 649 CD3_sp11a_VHVL_SW GFTFSKN 686 YYDSSK 689FSWDLDFDH 650 CD3_SP11A_VHVL_TT GFTFSKN 686 YYDSSK 689 FTTDLDFDH 651CD3_SP11A_VHVL_TW GFTFSKN 686 YYDSSK 689 FTWDLDFDH 652 CD3_SP11A_VHVL_WTGFTFSKN 686 YYDSSK 689 FWTDLDFDH 653 CD3_SP11A VH3_VLK_3 GFTFSKN 686YYDSSK 689 FWWDLDFDH 641 CD3_sp11a_VH1_VK2 GFTFSKQ 688 YYDSSK 689FWWDLDFDH 641 CD3_SP11A_VH3_VLK1 GFTFSKN 686 YYDSSK 689 FWWDLDFDH 641CD3_SP11A_VH5_VK2 GFTFSKQ 688 YYDSSK 689 FWWDLDFDH 641CD3_sp9aFW1_VL_VH_ GFSLTTY 599 RYSGD 601 DPMYIPNYAYG 654 S56G VMNACD3_SP9AFW4_VL_VH_ GFSLTTY 599 RYSGD 601 DPMYIPNYAYG 654 S56G VMNACD3_sp9aFW1_VLVH GFSLTTY 599 RYSGD 601 DPMYIPNYAYG 654 VMNACD3_sp9aFW4_VLVH GFSLTTY 599 RYSGD 601 DPMYIPNYAYG 654 VMNACD3_sp9arabtor_VHVL GFSLTTY 599 RYSGD 601 DPMYIPNYAYG 654 VMNACD3_sp9arabtor_VLVH GFSLTTY 599 RYSGD 601 DPMYIPNYAYG 654 VMNACD3_sp11 a_VHVL_YY_ GFTFSKQ 688 YYDSSK 689 FYYDLDFDH 647 SANSPTMCD3_sp11 a_VHVL_YY_ GFTFSKQ 688 YYDSSK 689 YYYDLDFDH 655 SANSPTM_YCD3_sp11 a_VHVL_YY_ GFTFSKQ 688 YYDSSK 689 SYYDLDFDH 656 SANSPTM_SCD3_sp11 a_VHVL_YY_Y GFTFSKN 686 YYDSSK 689 YYYDLDFDH 655CD3_sp11 a_VHVL_YY_s GFTFSKN 686 YYDSSK 689 SYYDLDFDH 656CD3_sp11 a_VHVL_SS_ GFTFSKQ 688 YYDSSK 689 FSSDLDFDH 648 SANSPTMCD3_sp11a_VHVL_SS_ GFTFSKQ 688 YYDSSK 689 YSSDLDFDH 657 SANSPTM_YCD3_sp11a_VHVL_SS_ GFTFSKQ 688 YYDSSK 689 SSSDLDFDH 658 SANSPTM_SCD3_sp11 a_VHVL_SS_Y GFTFSKN 686 YYDSSK 689 YSSDLDFDH 657CD3_sp11 a_VHVL_SS_S GFTFSKN 686 YYDSSK 689 SSSDLDFDH 658CD3_sp11a_VHVL_SS_ GFTFSKQ 688 YYDSSK 689 FSSDLDFDH 648 SANSPTMCD3_sp11a_VHVL_WS_ GFTFSKQ 688 YYDSSK 689 YWSDLDFDH 659 SANSPTM_YCD3_sp11a_VHVL_WS_ GFTFSKQ 688 YYDSSK 689 SWSDLDFDH 660 SANSPTM_SCD3_sp11a_VHVL_WS_ GFTFSKN 686 YYDSSK 689 YWSDLDFDH 659 YCD3_sp11a_VHVL_WS_ GFTFSKN 686 YYDSSK 689 SWSDLDFDH 660 SCD3_sp11a_VHVL_WS_ GFTFSKQ 688 YYDSSK 689 FWSDLDFDH 649 SANSPTMCD3_sp11a_VHVL_SW_ GFTFSKQ 688 YYDSSK 689 YSWDLDFDH 661 SANSPTM_YCD3_sp11a_VHVL_SW_ GFTFSKQ 688 YYDSSK 689 SSWDLDFDH 662 SANSPTM_SCD3_sp11a_VHVL_SW_ GFTFSKN 686 YYDSSK 689 YSWDLDFDH 661 YCD3_sp11a_VHVL_SW_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 SCD3_sp11a_VHVL_SW_ GFTFSKQ 688 YYDSSK 689 FSWDLDFDH 650 SANSPTMCD3_sp11a_VHVL_TW_ GFTFSKQ 688 YYDSSK 689 YTWDLDFDH 663 SANSPTM_YCD3_sp11a_VHVL_TW_ GFTFSKQ 688 YYDSSK 689 STWDLDFDH 664 SANSPTM_SCD3_sp11a_VHVL_TW_Y GFTFSKN 686 YYDSSK 689 YTWDLDFDH 663CD3_sp11a_VHVL_TW_S GFTFSKN 686 YYDSSK 689 STWDLDFDH 664CD3_sp11a_VHVL_TW_ GFTFSKQ 688 YYDSSK 689 FTWDLDFDH 652 SANSPTMCD3_sp11a_VHVL_TT_ GFTFSKQ 688 YYDSSK 689 YTTDLDFDH 665 SANSPTM_YCD3_sp11a_VHVL_TT_ GFTFSKQ 688 YYDSSK 689 STTDLDFDH 666 SANSPTM_SCD3_sp11a_VHVL_TT_Y GFTFSKN 686 YYDSSK 689 YTTDLDFDH 665CD3_sp11a_VHVL_TT_S GFTFSKN 686 YYDSSK 689 STTDLDFDH 666CD3_sp11a_VHVL_TT_ GFTFSKQ 688 YYDSSK 689 FTTDLDFDH 651 SANSPTMCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 YWWDLDFDH 667 YCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 SWWDLDFDH 668 SCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 YWWDLDFDH 667 Y_PTMCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 SWWDLDFDH 668 S_PTMCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 YSWDLDFDH 661 Y_SWCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 S_SWCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 YSWDLDFDH 661 Y_PTM_SWCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 S_SWPTMCD3_SP11AVH3_VLK_ GFTFSKN 686 YYDSSK 689 FSWDLDFDH 650 SWPTMCD3_SP11AVH3_VLK_3_ GFTFSKN 686 YYDSSK 689 FSWDLDFDH 650 SWCD3_sp11a_VH1_VK2_Y GFTFSKQ 688 YYDSSK 689 YWWDLDFDH 667CD3_sp11a_VH1_VK2_S GFTFSKQ 688 YYDSSK 689 SWWDLDFDH 668CD3_sp11a_VH1_VK2_Y_ GFTFSKN 686 YYDSSK 689 YWWDLDFDH 667 PTMCD3_sp11a_VH1_VK2_S_ GFTFSKN 686 YYDSSK 689 SWWDLDFDH 668 PTMCD3_sp11a_VH1_VK2_Y_ GFTFSKQ 688 YYDSSK 689 YSWDLDFDH 661 SWCD3_sp11a_VH1_VK2_S_ GFTFSKQ 688 YYDSSK 689 SSWDLDFDH 662 SWCD3_sp11a_VH1_VK2_Y_ GFTFSKN 686 YYDSSK 689 YSWDLDFDH 661 PTMCD3_sp11a_VH1_VK2_S_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 PTM_SWCD3_sp11a_VH1_VK2_SW GFTFSKQ 688 YYDSSK 689 FSWDLDFDH 650CD3_sp11a_VH1_VK2_ GFTFSKN 686 YYDSSK 689 FSWDLDFDH 650 SW_PTMCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 YWWDLDFDH 667 YCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 SWWDLDFDH 668 SCD3_SP11A_VH3_VLK1_ GFTFSKQ 688 YYDSSK 689 YWWDLDFDH 667 Y_PTMCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 SWWDLDFDH 668 S_PTMCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 YSWDLDFDH 661 Y_SWCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 S_SWCD3_SP11A_VH3_VLK1_ GFTFSKQ 688 YYDSSK 689 YWWDLDFDH 667 Y_PTMCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 S_PTM_SWCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 FSWDLDFDH 650 PTM_SWCD3_SP11A_VH3_VLK1_ GFTFSKN 686 YYDSSK 689 FSWDLDFDH 650 SWCD3_SP11A_VH5_VK2_Y GFTFSKQ 688 YYDSSK 689 YWWDLDFDH 667CD3_SP11A_VH5_VK2_S GFTFSKQ 688 YYDSSK 689 SWWDLDFDH 668CD3_SP11A_VH5_VK2_Y_ GFTFSKN 686 YYDSSK 689 YWWDLDFDH 667 PTMCD3_SP11A_VH5_VK2_S_ GFTFSKN 686 YYDSSK 689 SWWDLDFDH 668 PTMCD3_SP11A_VH5_VK2_Y_ GFTFSKQ 688 YYDSSK 689 YSWDLDFDH 661 SWCD3_SP11A_VH5_VK2_S_ GFTFSKQ 688 YYDSSK 689 SSWDLDFDH 662 SWCD3_SP11A_VH5_VK2_Y_ GFTFSKN 686 YYDSSK 689 YSWDLDFDH 661 PTM_SWCD3_SP11A_VH5_VK2_S_ GFTFSKN 686 YYDSSK 689 SSWDLDFDH 662 PTM_SWCD3_SP11A_VH5_VK2_ GFTFSKN 686 YYDSSK 689 FSWDLDFDH 650 PTM_SWCD3_SP11A_VH5_VK2_S GFTFSKQ 688 YYDSSK 689 FSWDLDFDH 650 W

TABLE AE-2 CD3 Binders- Light Chain CDR sequences according toChothia numbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2NO: CDR-L3 NO: NOV292 SQSLVRSD 693 RVS 625 SSHFPW 703 GTTY NOV123SQSLIYSI 694 RVS 625 STHLPY 627 GNTY Sp10b SQSLIYSI 694 RVS 625 STHLPY627 GNTY NOV453 SQNINNY 695 NTD 700 HRSRY 704 NOV229 SQNINNY 695 NTD 700HRSRY 704 NOV110 SQSLVYSH 696 RVS 625 STHLPY 627 GNTY NOV832 SQSLVYSH696 RVS 625 STHLPY 627 GNTY NOV589 SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYNOV580 SQNIDKY 697 NTN 701 HRSSY 705 NOV567 SQSIGNS 698 STS 702 YATYPY706 NOV221 SQNIDKY 697 NTN 701 HRSGY 707 CD3_sp11a_bkm1 SQSLVRSD 693 RVS625 SSHFPW 703 GTTY CD3_SP11a_bkm2 SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11_a_hz0 SQSLVRSD 693 RVS 625 SSHFPW 703 GTTY CD3_SP11A_HZ1SQSLVRSD 693 RVS 625 SSHFPW 703 GTTY CD3_sp11a_sansPTM_hz1 SQSLVRSE 699RVS 625 SSHFPW 703 GTTY CD3_sp11a_sansPTM_rat SQSLVRSE 699 RVS 625SSHFPW 703 GTTY CD3_sp11a_VHVL_YY SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VHVL_SS SQSLVRSD 693 RVS 625 SSHFPW 703 GTTY CD3_SP11A_VHVL_WSSQSLVRSD 693 RVS 625 SSHFPW 703 GTTY CD3_sp11a_VHVL_SW SQSLVRSD 693 RVS625 SSHFPW 703 GTTY CD3_SP11A_VHVL_TT SQSLVRSD 693 RVS 625 SSHFPW 703GTTY CD3_SP11A_VHVL_TW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VHVL_WT SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A VH3_VLK_3 SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2 SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1 SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2 SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp9aFW1_VL_VH_S56G SQNINNY 695 NTD 700 HRSRY 704CD3_SP9AFW4_VL_VH_S56G SQNINNY 695 NTD 700 HRSRY 704 CD3_sp9aFW1_VLVHSQNINNY 695 NTD 700 HRSRY 704 CD3_sp9aFW4_VLVH SQNINNY 695 NTD 700 HRSRY704 CD3_sp9arabtor_VHVL SQNINNY 695 NTD 700 HRSRY 704CD3_sp9arabtor_VLVH SQNINNY 695 NTD 700 HRSRY 704CD3_sp11a_VHVL_YY_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_YY_SANSPTM_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_YY_SANSPTM_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_YY_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_YY_s SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SS_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SS_SANSPTM_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SS_SANSPTM_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SS_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SS_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SS_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_WS_SANSPTM_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_WS_SANSPTM_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_WS_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_WS_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_WS_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SW_SANSPTM_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SW_SANSPTM_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SW_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SW_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_SW_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TW_SANSPTM_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TW_SANSPTM_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TW_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TW_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TW_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TT_SANSPTM_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TT_SANSPTM_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TT_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TT_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VHVL_TT_SANSPTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_Y_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_S_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_Y_SW SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_S_SW SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_Y_PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_S_SWPTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_SWPTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11AVH3_VLK_3_SW SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_Y_PTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_S_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_Y_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_S_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_Y_PTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_S_PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_sp11a_VH1_VK2_SW_PTM SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_Y SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_S SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_Y_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_S_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_Y_SW SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_S_SW SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_Y_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_S_PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH3_VLK1_SW SQSLVRSE 699 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_Y SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_S SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_Y_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_S_PTM SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_Y_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_S_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_Y_PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_S_PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_PTM_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTYCD3_SP11A_VH5_VK2_SW SQSLVRSD 693 RVS 625 SSHFPW 703 GTTY

TABLE AF-1 CD3 Binders- Heavy Chain CDR sequences according toIMGT numbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-H1 NO: CDR-H2 NO:CDR-H3 NO: NOV292 GFTFSKN 708 IYYDSSKM 711 ASFWWDLDF 715 G DH NOV123GYTFTSY 614 IYPGHDAI 712 VRPNTMMAP 716 Y LAY Sp10b GYTFTSY 614 IYPGHDAI712 VRPNTMMAP 716 Y LAY NOV453 GFSLTTY 597 MRYSGDT 602 TSDPMYIPN 717 NYSYGVMNA NOV229 GFSLTTY 597 MRYSGDT 602 ARDPMYIPN 718 N YSYGVMNA NOV110GYTFTSY 614 IYPANGGI 713 ARPVTMMAP 719 Y LVF NOV832 GYTFTSY 614 IYPANGGI713 ARPVTMMAP 719 Y LVF NOV589 GFTFSKN 708 IYYDSSRM 714 ASFWWDLDF 720 GDY NOV580 GFSLTTY 597 MRYSGDT 602 TRDPMYIPG 721 N YSYGVMNA NOV567GFAFRKY 709 IYYDSSKM 711 AALNSEYD 582 G NOV221 GFSLTTY 597 MRYSGDT 602TRDPMYIPG 721 N YSYGVMNA CD3_sp11a_bkm1 GFTFSKN 708 IYYDSSKM 711ASFWWDLDF 715 G DH CD3_SP11a_bkm2 GFTFSKN 708 IYYDSSKM 711 AKFWWDLDF 722G DH CD3_sp11a_hz0 GFTFSKN 708 IYYDSSKM 711 AKFWWDLDF 722 G DHCD3_SP11A_HZ1 GFTFSKN 708 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_sp11a_sansPTM_hz1 GFTFSKQ 710 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_sp11a_sansPTM_rat GFTFSKQ 710 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_sp11a_VHVL_YY GFTFSKN 708 IYYDSSKM 711 ASFYYDLDF 723 G DHCD3_SP11A_VHVL_SS GFTFSKN 708 IYYDSSKM 711 ASFSSDLDF 724 G DHCD3_SP11A_VHVL_WS GFTFSKN 708 IYYDSSKM 711 ASFWSDLDF 725 G DHCD3_sp11a_VHVL_SW GFTFSKN 708 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_SP11A_VHVL_TT GFTFSKN 708 IYYDSSKM 711 ASFTTDLDF 727 G DHCD3_SP11A_VHVL_TW GFTFSKN 708 IYYDSSKM 711 ASFTWDLDF 728 G DHCD3_SP11A_VHVL_WT GFTFSKN 708 IYYDSSKM 711 ASFWTDLDF 729 G DHCD3_SP11A VH3_VLK_3 GFTFSKN 708 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_sp11a_VH1_VK2 GFTFSKQ 710 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_SP11A_VH3_VLK1 GFTFSKN 708 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_SP11A_VH5_VK2 GFTFSKQ 710 IYYDSSKM 711 ASFWWDLDF 715 G DHCD3_sp9aFW1_VL_VH_S56G GFSLTTY 597 MRYSGDT 602 ASDPMYIPN 730 N YAYGVMNACD3_SP9AFW4_VL_VH_S56G GFSLTTY 597 MRYSGDT 602 ASDPMYIPN 730 N YAYGVMNACD3_sp9aFW1_VLVH GFSLTTY 597 MRYSGDT 602 ASDPMYIPN 730 N YAYGVMNACD3_sp9aFW4_VLVH GFSLTTY 597 MRYSGDT 602 ASDPMYIPN 730 N YAYGVMNACD3_sp9arabtor_VHVL GFSLTTY 597 MRYSGDT 602 ASDPMYIPN 730 N YAYGVMNACD3_sp9arabtor_VLVH GFSLTTY 597 MRYSGDT 602 ASDPMYIPN 730 N YAYGVMNACD3_sp11a_VHVL_YY_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFYYDLDF 723 G DHCD3_sp11a_VHVL_YY_SANSPTM_Y GFTFSKQ 710 IYYDSSKM 711 ASYYYDLDF 731 G DHCD3_sp11a_VHVL_YY_SANSPTM_S GFTFSKQ 710 IYYDSSKM 711 ASSYYDLDF 732 G DHCD3_sp11a_VHVL_YY_Y GFTFSKN 708 IYYDSSKM 711 ASYYYDLDF 731 G DHCD3_sp11a_VHVL_YY_s GFTFSKN 708 IYYDSSKM 711 ASSYYDLDF 732 G DHCD3_sp11a_VHVL_SS_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFSSDLDF 724 G DHCD3_sp11a_VHVL_SS_SANSPTM_Y GFTFSKQ 710 IYYDSSKM 711 ASYSSDLDF 733 G DHCD3_sp11a_VHVL_SS_SANSPTM_S GFTFSKQ 710 IYYDSSKM 711 ASSSSDLDF 734 G DHCD3_sp11a_VHVL_SS_Y GFTFSKN 708 IYYDSSKM 711 ASYSSDLDF 733 G DHCD3_sp11a_VHVL_SS_S GFTFSKN 708 IYYDSSKM 711 ASSSSDLDF 734 G DHCD3_sp11a_VHVL_SS_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFSSDLDF 724 G DHCD3_sp11a_VHVL_WS_SANSPTM_Y GFTFSKQ 710 IYYDSSKM 711 ASYWSDLDF 735 G DHCD3_sp11a_VHVL_WS_SANSPTM_S GFTFSKQ 710 IYYDSSKM 711 ASSWSDLDF 736 G DHCD3_sp11a_VHVL_WS_Y GFTFSKN 708 IYYDSSKM 711 ASYWSDLDF 735 G DHCD3_sp11a_VHVL_WS_S GFTFSKN 708 IYYDSSKM 711 ASSWSDLDF 736 G DHCD3_sp11a_VHVL_WS_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFWSDLDF 725 G DHCD3_sp11a_VHVL_SW_SANSPTM_Y GFTFSKQ 710 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_sp11a_VHVL_SW_SANSPTM_S GFTFSKQ 710 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_sp11a_VHVL_SW_Y GFTFSKN 708 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_sp11a_VHVL_SW_S GFTFSKN 708 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_sp11a_VHVL_SW_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_sp11a_VHVL_TW_SANSPTM_Y GFTFSKQ 710 IYYDSSKM 711 ASYTWDLDF 739 G DHCD3_sp11a_VHVL_TW_SANSPTM_S GFTFSKQ 710 IYYDSSKM 711 ASSTWDLDF 740 G DHCD3_sp11a_VHVL_TW_Y GFTFSKN 708 IYYDSSKM 711 ASYTWDLDF 739 G DHCD3_sp11a_VHVL_TW_S GFTFSKN 708 IYYDSSKM 711 ASSTWDLDF 740 G DHCD3_sp11a_VHVL_TW_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFTWDLDF 728 G DHCD3_sp11a_VHVL_TT_SANSPTM_Y GFTFSKQ 710 IYYDSSKM 711 ASYTTDLDF 741 G DHCD3_sp11a_VHVL_TT_SANSPTM_S GFTFSKQ 710 IYYDSSKM 711 ASSTTDLDF 742 G DHCD3_sp11a_VHVL_TT_Y GFTFSKN 708 IYYDSSKM 711 ASYTTDLDF 741 G DHCD3_sp11a_VHVL_TT_S GFTFSKN 708 IYYDSSKM 711 ASSTTDLDF 742 G DHCD3_sp11a_VHVL_TT_SANSPTM GFTFSKQ 710 IYYDSSKM 711 ASFTTDLDF 727 G DHCD3_SP11AVH3_VLK_3_Y GFTFSKN 708 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11AVH3_VLK_3_S GFTFSKN 708 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_SP11AVH3_VLK_3_Y_PTM GFTFSKN 708 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11AVH3_VLK_3_S_PTM GFTFSKN 708 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_SP11AVH3_VLK_3_Y_SW GFTFSKN 708 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_SP11AVH3_VLK_3_S_SW GFTFSKN 708 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_SP11AVH3_VLK_3_Y_PTM_SW GFTFSKN 708 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_SP11AVH3_VLK_3_S_SWPTM GFTFSKN 708 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_SP11AVH3_VLK_SWPTM GFTFSKN 708 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_SP11AVH3_VLK_3_SW GFTFSKN 708 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_sp11a_VH1_VK2_Y GFTFSKQ 710 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_sp11a_VH1_VK2_S GFTFSKQ 710 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_sp11a_VH1_VK2_Y_PTM GFTFSKN 708 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_sp11a_VH1_VK2_S_PTM GFTFSKN 708 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_sp11a_VH1_VK2_Y_SW GFTFSKQ 710 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_sp11a_VH1_VK2_S_SW GFTFSKQ 710 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_sp11a_VH1_VK2_Y_PTM GFTFSKN 708 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_sp11a_VH1_VK2_S_PTM_SW GFTFSKN 708 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_sp11a_VH1_VK2_SW GFTFSKQ 710 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_sp11a_VH1_VK2_SW_PTM GFTFSKN 708 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_SP11A_VH3_VLK1_Y GFTFSKN 708 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11A_VH3_VLK1_S GFTFSKN 708 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_SP11A_VH3_VLK1_Y_PTM GFTFSKQ 710 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11A_VH3_VLK1_S_PTM GFTFSKQ 710 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_SP11A_VH3_VLK1_Y_SW GFTFSKN 708 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_SP11A_VH3_VLK1_S_SW GFTFSKN 708 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_SP11A_VH3_VLK1_Y_PTM GFTFSKQ 710 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11A_VH3_VLK1_S_PTM_SW GFTFSKQ 710 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_SP11A_VH3_VLK1PTM_SW GFTFSKQ 710 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_SP11A_VH3_VLK1_SW GFTFSKN 708 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_SP11A_VH5_VK2_Y GFTFSKQ 710 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11A_VH5_VK2_S GFTFSKQ 710 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_SP11A_VH5_VK2_Y_PTM GFTFSKN 708 IYYDSSKM 711 ASYWWDLDF 743 G DHCD3_SP11A_VH5_VK2_S_PTM GFTFSKN 708 IYYDSSKM 711 ASSWWDLDF 744 G DHCD3_SP11A_VH5_VK2_Y_SW GFTFSKQ 710 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_SP11A_VH5_VK2_S_SW GFTFSKQ 710 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_SP11A_VH5_VK2_Y_PTM_SW GFTFSKN 708 IYYDSSKM 711 ASYSWDLDF 737 G DHCD3_SP11A_VH5_VK2_S_PTM_SW GFTFSKN 708 IYYDSSKM 711 ASSSWDLDF 738 G DHCD3_SP11A_VH5_VK2_PTM_SW GFTFSKN 708 IYYDSSKM 711 ASFSWDLDF 726 G DHCD3_SP11A_VH5_VK2_SW GFTFSKQ 710 IYYDSSKM 711 ASFSWDLDF 726 G DH

TABLE AF-2 CD3 Binders- Light Chain CDR sequences according toIMGT numbering scheme SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2 NO:CDR-L3 NO: NOV292 QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWT NOV123 QSLIYSI746 RVS 625 FQSTHL 626 GNTY PYT Sp10b QSLIYSI 746 RVS 625 FQSTHL 626GNTY PYT NOV453 QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YT NOV229 QNINNY747 NTDHLQA 753 LQHRSR 681 GVP YT NOV110 QSLVYSH 748 RVS 625 FQSTHL 626GNTY PYT NOV832 QSLVYSH 748 RVS 625 FQSTHL 626 GNTY PYT NOV589 QSLVRSD745 RVS 625 LQSSHF 680 GTTY PWT NOV580 QNIDKY 749 NTNNLEA 754 LQHRSS 682GVP YT NOV567 QSIGNS 750 STSTLEY 755 LQYATY 683 GVP PYT NOV221 QNIDKY749 NTNNLEA 754 LQHRSG 684 GVP YT CD3_sp11a_bkm1 QSLVRSD 745 RVS 625LQSSHF 680 GTTY PWT CD3_SP11a_bkm2 QSLVRSD 745 RVS 625 LQSSHF 680 GTTYPWT CD3_sp11a_hz0 QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWT CD3_SP11A_HZ1QSLVRSD 745 RVS 625 LQSSH 685 GTTY CD3_sp11a_sansPTM_hz1 QSLVRSE 751 RVS625 LQSSHF 680 GTTY PWT CD3_sp11a_sansPTM_rat QSLVRSE 751 RVS 625 LQSSHF680 GTTY PWT CD3_sp11a_VHVL_YY QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_SS QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_WS QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_TT QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_TW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_WT QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A VH3_VLK_3 QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2 QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1 QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2 QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp9aFW1_VL_VH_S56G QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YTCD3_SP9AFW4_VL_VH_S56G QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9aFW1_VLVH QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9aFW4_VLVH QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9arabtor_VHVL QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9arabtor_VLVH QNINNY 747 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp11a_VHVL_YY_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_YY_SANSPTM_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_YY_SANSPTM_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_YY_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_YY_s QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SS_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SS_SANSPTM_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SS_SANSPTM_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SS_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SS_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SS_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_WS_SANSPTM_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_WS_SANSPTM_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_WS_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_WS_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_WS_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW_SANSPTM_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW_SANSPTM_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TW_SANSPTM_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TW_SANSPTM_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TW_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TW_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TW_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TT_SANSPTM_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TT_SANSPTM_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TT_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TT_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_TT_SANSPTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_Y_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_S_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_Y_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_S_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_Y_PTM_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_S_SWPTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_SWPTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11AVH3_VLK_3_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_Y_PTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_S_PTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_Y_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_S_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_Y_PTM QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_S_PTM_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_SW_PTM QSLVRSD 752 RVS 625 LQSSHF 680 ETTY PWTCD3_SP11A_VH3_VLK1_Y QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_S QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_Y_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_S_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_Y_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_S_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_Y_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_S_PTM_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1PTM_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1_SW QSLVRSE 751 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_Y QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_S QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_Y_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_S_PTM QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_Y_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_S_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_Y_PTM_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_S_PTM_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_PTM_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_SW QSLVRSD 745 RVS 625 LQSSHF 680 GTTY PWT

TABLE AG-1CD3 Binders- Heavy Chain CDR sequences according to combinationof Kabat and Chothia numbering schemes SEQ ID SEQ ID SEQ ID BinderCDR-H1 NO: CDR-H2 NO: CDR-H3 NO: NOV292 GFTFSK 756 MIYYDSSKMY 634FWWDLDFDH 641 NGMH YADTVKG NOV123 GYTFTS 613 YIYPGHDAIY 635 PNTMMAPLA642 YYIY YSENFKG Y Sp10b GYTFTS 613 YIYPGHDAIY 635 PNTMMAPLA 642 YYIYYSENFKG Y NOV453 GFSLTT 757 RMRYSGDTSF 636 DPMYIPNYS 643 YNVH NAALTSYGVMNA NOV229 GFSLTT 757 RMRYSGDTSF 636 DPMYIPNYS 643 YNVH NAALTS YGVMNANOV110 GYTFTS 613 YIYPANGGIY 637 PVTMMAPLV 644 YYIY YSEKFKG F NOV832GYTFTS 613 YIYPANGGIY 637 PVTMMAPLV 644 YYIY YSEKFKG F NOV589 GFTFSK 756MIYYDSSRMY 638 FWWDLDFDY 645 NGMH YADTVKG NOV580 GFSLTT 758 RMRYSGDTSY639 DPMYIPGYS 646 YNIH SSALKS YGVMNA NOV567 GFAFRK 759 LIYYDSSKMN 640LNSEYD 583 YGMS YADTVKG NOV221 GFSLTT 758 RMRYSGDTSY 639 DPMYIPGYS 646YNIH SSALKS YGVMNA CD3_sp11a_bkm1 GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH641 NGMH YADTVKG CD3_SP11a_bkm2 GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641NGMH YADTVKG CD3_sp11a_hz0 GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMHYADTVKG CD3_SP11A_HZ1 GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMHYADTVKG CD3_sp11a_sansPTM_hz1 GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641QGMH YADTVKG CD3_sp11a_sansPTM_rat GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH641 QGMH YADTVKG CD3_sp11a_VHVL_YY GFTFSK 756 MIYYDSSKMY 634 FYYDLDFDH647 NGMH YADTVKG CD3_SP11A_VHVL_SS GFTFSK 756 MIYYDSSKMY 634 FSSDLDFDH648 NGMH YADTVKG CD3_SP11A_VHVL_WS GFTFSK 756 MIYYDSSKMY 634 FWSDLDFDH649 NGMH YADTVKG CD3_sp11a_VHVL_SW GFTFSK 756 MIYYDSSKMY 634 FSWDLDFDH650 NGMH YADTVKG CD3_SP11A_VHVL_TT GFTFSK 756 MIYYDSSKMY 634 FTTDLDFDH651 NGMH YADTVKG CD3_SP11A_VHVL_TW GFTFSK 756 MIYYDSSKMY 634 FTWDLDFDH652 NGMH YADTVKG CD3_SP11A_VHVL_WT GFTFSK 756 MIYYDSSKMY 634 FWTDLDFDH653 NGMH YADTVKG CD3_SP11A VH3_VLK_3 GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH641 NGMH YADTVKG CD3_sp11a_VH1_VK2 GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH641 QGMH YADTVKG CD3_SP11A_VH3_VLK1 GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH641 NGMH YADTVKG CD3_SP11A_VH5_VK2 GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH641 QGMH YADTVKG CD3_sp9aFW1_VL_VH_S56G GFSLTT 757 RMRYSGDTSF 636DPMYIPNYA 654 YNVH NAALTS YGVMNA CD3_SP9AFW4_VL_VH_S56G GFSLTT 757RMRYSGDTSF 636 DPMYIPNYA 654 YNVH NAALTS YGVMNA CD3_sp9aFW1_VLVH GFSLTT757 RMRYSGDTSF 636 DPMYIPNYA 654 YNVH NAALTS YGVMNA CD3_sp9aFW4_VLVHGFSLTT 757 RMRYSGDTSF 636 DPMYIPNYA 654 YNVH NAALTS YGVMNACD3_sp9arabtor_VHVL GFSLTT 757 RMRYSGDTSF 636 DPMYIPNYA 654 YNVH NAALTSYGVMNA CD3_sp9arabtor_VLVH GFSLTT 757 RMRYSGDTSF 636 DPMYIPNYA 654 YNVHNAALTS YGVMNA CD3_sp11a_VHVL_YY_SANSPTM GFTFSK 760 MIYYDSSKMY 634FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_YY_SANSPTM_Y GFTFSK 760MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_YY_SANSPTM_SGFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_YY_YGFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMH YADTVKG CD3_sp11a_VHVL_YY_sGFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMH YADTVKGCD3_sp11a_VHVL_SS_SANSPTM GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMHYADTVKG CD3_sp11a_VHVL_SS_SANSPTM_Y GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH641 QGMH YADTVKG CD3_sp11a_VHVL_SS_SANSPTM_S GFTFSK 760 MIYYDSSKMY 634FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_SS_Y GFTFSK 756 MIYYDSSKMY 634FWWDLDFDH 641 NGMH YADTVKG CD3_sp11a_VHVL_SS_S GFTFSK 756 MIYYDSSKMY 634FWWDLDFDH 641 NGMH YADTVKG CD3_sp11a_VHVL_SS_SANSPTM GFTFSK 760MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_WS_SANSPTM_YGFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKGCD3_sp11a_VHVL_WS_SANSPTM_S GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMHYADTVKG CD3_sp11a_VHVL_WS_Y GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMHYADTVKG CD3_sp11a_VHVL_WS_S GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMHYADTVKG CD3_sp11a_VHVL_WS_SANSPTM GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH641 QGMH YADTVKG CD3_sp11a_VHVL_SW_SANSPTM_Y GFTFSK 760 MIYYDSSKMY 634FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_SW_SANSPTM_S GFTFSK 760MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_SW_Y GFTFSK 756MIYYDSSKMY 634 FWWDLDFDH 641 NGMH YADTVKG CD3_sp11a_VHVL_SW_S GFTFSK 756MIYYDSSKMY 634 FWWDLDFDH 641 NGMH YADTVKG CD3_sp11a_VHVL_SW_SANSPTMGFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKGCD3_sp11a_VHVL_TW_SANSPTM_Y GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMHYADTVKG CD3_sp11a_VHVL_TW_SANSPTM_S GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH641 QGMH YADTVKG CD3_sp11a_VHVL_TW_Y GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH641 NGMH YADTVKG CD3_sp11a_VHVL_TW_S GFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH641 NGMH YADTVKG CD3_sp11a_VHVL_TW_SANSPTM GFTFSK 760 MIYYDSSKMY 634FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_TT_SANSPTM_Y GFTFSK 760MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_TT_SANSPTM_SGFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMH YADTVKG CD3_sp11a_VHVL_TT_YGFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMH YADTVKG CD3_sp11a_VHVL_TT_SGFTFSK 756 MIYYDSSKMY 634 FWWDLDFDH 641 NGMH YADTVKGCD3_sp11a_VHVL_TT_SANSPTM GFTFSK 760 MIYYDSSKMY 634 FWWDLDFDH 641 QGMHYADTVKG CD3_SP11AVH3_VLK_3_Y GFTFSK 756 MIYYDSSKMY 634 YWWDLDFDH 667NGMH YADTVKG CD3_SP11AVH3_VLK_3_S GFTFSK 756 MIYYDSSKMY 634 SWWDLDFDH668 NGMH YADTVKG CD3_SP11AVH3_VLK_3_Y_PTM GFTFSK 756 MIYYDSSKMY 634YWWDLDFDH 667 NGMH YADTVKG CD3_SP11AVH3_VLK_3_S_PTM GFTFSK 756MIYYDSSKMY 634 SWWDLDFDH 668 NGMH YADTVKG CD3_SP11AVH3_VLK_3_Y_SW GFTFSK756 MIYYDSSKMY 634 YSWDLDFDH 661 NGMH YADTVKG CD3_SP11AVH3_VLK_3_S_SWGFTFSK 756 MIYYDSSKMY 634 SSWDLDFDH 662 NGMH YADTVKGCD3_SP11AVH3_VLK_3_Y_PTM_SW GFTFSK 756 MIYYDSSKMY 634 YSWDLDFDH 661 NGMHYADTVKG CD3_SP11AVH3_VLK_3_S_SWPTM GFTFSK 756 MIYYDSSKMY 634 SSWDLDFDH662 NGMH YADTVKG CD3_SP11AVH3_VLK_SWPTM GFTFSK 756 MIYYDSSKMY 634FSWDLDFDH 650 NGMH YADTVKG CD3_SP11AVH3_VLK_3_SW GFTFSK 756 MIYYDSSKMY634 FSWDLDFDH 650 NGMH YADTVKG CD3_sp11a_VH1_VK2_Y GFTFSK 760 MIYYDSSKMY634 YWWDLDFDH 667 QGMH YADTVKG CD3_sp11a_VH1_VK2_s GFTFSK 760 MIYYDSSKMY634 SWWDLDFDH 668 QGMH YADTVKG CD3_sp11a_VH1_VK2_Y_PTM GFTFSK 756MIYYDSSKMY 634 YWWDLDFDH 667 NGMH YADTVKG CD3_sp11a_VH1_VK2_S_PTM GFTFSK756 MIYYDSSKMY 634 SWWDLDFDH 668 NGMH YADTVKG CD3_sp11a_VH1_VK2_Y_SWGFTFSK 760 MIYYDSSKMY 634 YSWDLDFDH 661 QGMH YADTVKGCD3_sp11a_VH1_VK2_S_SW GFTFSK 760 MIYYDSSKMY 634 SSWDLDFDH 662 QGMHYADTVKG CD3_sp11a_VH1_VK2_Y_PTM GFTFSK 756 MIYYDSSKMY 634 YSWDLDFDH 661NGMH YADTVKG CD3_sp11a_VH1_VK2_S_PTM_SW GFTFSK 756 MIYYDSSKMY 634SSWDLDFDH 662 NGMH YADTVKG CD3_sp11a_VH1_VK2_SW GFTFSK 760 MIYYDSSKMY634 FSWDLDFDH 650 QGMH YADTVKG CD3_sp11a_VH1_VK2_SW_PTM GFTFSK 756MIYYDSSKMY 634 FSWDLDFDH 650 NGMH YADTVKG CD3_SP11A_VH3_VLK1_Y GFTFSK756 MIYYDSSKMY 634 YWWDLDFDH 667 NGMH YADTVKG CD3_SP11A_VH3_VLK1_SGFTFSK 756 MIYYDSSKMY 634 SWWDLDFDH 668 NGMH YADTVKGCD3_SP11A_VH3_VLK1_Y_PTM GFTFSK 760 MIYYDSSKMY 634 YWWDLDFDH 667 QGMHYADTVKG CD3_SP11A_VH3_VLK1_S_PTM GFTFSK 760 MIYYDSSKMY 634 SWWDLDFDH 668QGMH YADTVKG CD3_SP11A_VH3_VLK1_Y_SW GFTFSK 756 MIYYDSSKMY 634 YSWDLDFDH661 NGMH YADTVKG CD3_SP11A_VH3_VLK1_S_SW GFTFSK 756 MIYYDSSKMY 634SSWDLDFDH 662 NGMH YADTVKG CD3_SP11A_VH3_VLK1_Y_PTM GFTFSK 760MIYYDSSKMY 634 YWWDLDFDH 667 QGMH YADTVKG CD3_SP11A_VH3_VLK1_S_PTM_SWGFTFSK 760 MIYYDSSKMY 634 SSWDLDFDH 662 QGMH YADTVKGCD3_SP11A_VH3_VLK1PTM_SW GFTFSK 760 MIYYDSSKMY 634 FSWDLDFDH 650 QGMHYADTVKG CD3_SP11A_VH3_VLK1_SW GFTFSK 756 MIYYDSSKMY 634 FSWDLDFDH 650NGMH YADTVKG CD3_SP11A_VH5_VK2_Y GFTFSK 760 MIYYDSSKMY 634 YWWDLDFDH 667QGMH YADTVKG CD3_SP11A_VH5_VK2_S GFTFSK 760 MIYYDSSKMY 634 SWWDLDFDH 668QGMH YADTVKG CD3_SP11A_VH5_VK2_Y_PTM GFTFSK 756 MIYYDSSKMY 634 YWWDLDFDH667 NGMH YADTVKG CD3_SP11A_VH5_VK2_S_PTM GFTFSK 756 MIYYDSSKMY 634SWWDLDFDH 668 NGMH YADTVKG CD3_SP11A_VH5_VK2_Y_SW GFTFSK 760 MIYYDSSKMY634 YSWDLDFDH 661 QGMH YADTVKG CD3_SP11A_VH5_VK2_S_SW GFTFSK 760MIYYDSSKMY 634 SSWDLDFDH 662 QGMH YADTVKG CD3_SP11A_VH5_VK2_Y_PTM_SWGFTFSK 756 MIYYDSSKMY 634 YSWDLDFDH 661 NGMH YADTVKGCD3_SP11A_VH5_VK2_S_PTM_SW GFTFSK 756 MIYYDSSKMY 634 SSWDLDFDH 662 NGMHYADTVKG CD3_SP11A_VH5_VK2_PTM_SW GFTFSK 756 MIYYDSSKMY 634 FSWDLDFDH 650NGMH YADTVKG CD3_SP11A_VH5_VK2_SW GFTFSK 760 MIYYDSSKMY 634 FSWDLDFDH650 QGMH YADTVKG

TABLE AG-2 CD3 Binders- Light Chain CDR sequences according to  combination of Kabat and Chothia numbering schemes SEQ ID CDR- SEQ IDSEQ ID Binder CDR-L1 NO: L2 NO: CDR-L3 NO: NOV292 RSSQSLVRSD 669 RVSN624 LQSSHFP 680 GTTYFN RFS WT NOV123 RSSQSLIYSIGN 670 RVSN 624 FQSTHLP626 TYLH RFS YT Sp10b RSSQSLIYSIGN 670 RVSN 624 FQSTHLP 626 TYLH RFS YTNOV453 KASQNINNYLN 671 NTDH 677 LQHRSR 681 LQA YT NOV229 KASQNINNYLN 671NTDH 677 LQHRSR 681 LQA YT NOV110 RSSQSLVYSH 672 RVSN 624 FQSTHLP 626GNTYLH RFS YT NOV832 RSSQSLVYSH 672 RVSN 624 FQSTHLP 626 GNTYLH RFS YTNOV589 RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WT NOV580KTSQNIDKYLN 673 NTNN 678 LQHRSS 682 LEA YT NOV567 RGSQSIGNSLN 674 STSTL679 LQYATYP 683 EY YT NOV221 KSSQNIDKYLN 675 NTNN 678 LQHRSG 684 LEA YTCD3_sp11a_bkm1 RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11a_bkm2 RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11_a_hz0 RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_HZ1 RSSQSLVRSD 669 RVSN 624 LQSSH 685 GTTYFN RFSCD3_sp11a_sansPTM_hz1 RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11a_sansPTM_rat RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11a_VHVL_YY RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VHVL_SS RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VHVL_WS RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11a_VHVL_SW RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VHVL_TT RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VHVL_TW RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VHVL_WT RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A VH3_VLK_3 RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11a_VH1_VK2 RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VH3_VLK1 RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_SP11A_VH5_VK2 RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp9aFW1_VL_VH_S5 KASQNINNYLN 671 NTDH 677 LQHRSR 681 6G LQA YTCD3_SP9AFW4_VL_VH_S KASQNINNYLN 671 NTDH 677 LQHRSR 681 56G LQA YTCD3_sp9aFW1_VLVH KASQNINNYLN 671 NTDH 677 LQHRSR 681 LQA YTCD3_sp9aFW4_VLVH KASQNINNYLN 671 NTDH 677 LQHRSR 681 LQA YTCD3_sp9arabtor_VHVL KASQNINNYLN 671 NTDH 677 LQHRSR 681 LQA YTCD3_sp9arabtor_VLVH KASQNINNYLN 671 NTDH 677 LQHRSR 681 LQA YTCD3_sp11a_VHVL_YY_SA RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 NSPTM GTTYFNRFS WT CD3_sp11a_VHVL_YY_SA RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 NSPTM_YGTTYFN RFS WT CD3_sp11a_VHVL_YY_SA RSSQSLVRSE 676 RVSN 624 LQSSHFP 680NSPTM_S GTTYFN RFS WT CD3_sp11a_VHVL_YY_Y RSSQSLVRSD 669 RVSN 624LQSSHFP 680 GTTYFN RFS WT CD3_sp11a_VHVL_YY_s RSSQSLVRSD 669 RVSN 624LQSSHFP 680 GTTYFN RFS WT CD3_sp11a_VHVL_SS_SA RSSQSLVRSE 676 RVSN 624LQSSHFP 680 NSPTM GTTYFN RFS WT CD3_sp11a_VHVL_SS_SA RSSQSLVRSE 676 RVSN624 LQSSHFP 680 NSPTM_Y GTTYFN RFS WT CD3_sp11a_VHVL_SS_SA RSSQSLVRSE676 RVSN 624 LQSSHFP 680 NSPTM_S GTTYFN RFS WT CD3_sp11a_VHVL_SS_YRSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WT CD3_sp11a_VHVL_SS_SRSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WT CD3_sp11a_VHVL_SSRSSQSLVRSE 676 RVSN 624 LQSSHFP 680 _SANSPTM GTTYFN RFS WTCD3_sp11a_VHVL_WS RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 _SANSPTM_Y GTTYFNRFS WT CD3_sp11a_VHVL_WS RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 _SANSPTM_SGTTYFN RFS WT CD3_sp11a_VHVL_WS RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 _YGTTYFN RFS WT CD3_sp11a_VHVL_WS RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 _SGTTYFN RFS WT CD3_sp11a_VHVL_WS RSSQSLVRSE 676 RVSN 624 LQSSHFP 680_SANSPTM GTTYFN RFS WT CD3_sp11a_VHVL_SW RSSQSLVRSE 676 RVSN 624 LQSSHFP680 _SANSPTM_Y GTTYFN RFS WT CD3_sp11a_VHVL_SW RSSQSLVRSE 676 RVSN 624LQSSHFP 680 _SANSPTM_S GTTYFN RFS WT CD3_sp11a_VHVL_SW RSSQSLVRSD 669RVSN 624 LQSSHFP 680 _Y GTTYFN RFS WT CD3_sp11a_VHVL_SW RSSQSLVRSD 669RVSN 624 LQSSHFP 680 _S GTTYFN RFS WT CD3_sp11a_VHVL_SW RSSQSLVRSE 676RVSN 624 LQSSHFP 680 _SANSPTM GTTYFN RFS WT CD3_sp11a_VHVL_TW RSSQSLVRSE676 RVSN 624 LQSSHFP 680 _SANSPTM_Y GTTYFN RFS WT CD3_sp11a_VHVL_TWRSSQSLVRSE 676 RVSN 624 LQSSHFP 680 _SANSPTM_S GTTYFN RFS WTCD3_sp11a_VHVL_TW_Y RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11a_VHVL_TW_S RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WTCD3_sp11a_VHVL_TW RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 _SANSPTM GTTYFNRFS WT CD3_sp11a_VHVL_TT RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 _SANSPTM_YGTTYFN RFS WT CD3_sp11a_VHVL_TT_SA RSSQSLVRSE 676 RVSN 624 LQSSHFP 680NSPTM_S GTTYFN RFS WT CD3_sp11a_VHVL_TT_Y RSSQSLVRSD 669 RVSN 624LQSSHFP 680 GTTYFN RFS WT CD3_sp11a_VHVL_TT_S RSSQSLVRSD 669 RVSN 624LQSSHFP 680 GTTYFN RFS WT CD3_sp11a_VHVL_TT_SA RSSQSLVRSE 676 RVSN 624LQSSHFP 680 NSPTM GTTYFN RFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSE 676 RVSN624 LQSSHFP 680 Y GTTYFN RFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSE 676 RVSN624 LQSSHFP 680 S GTTYFN RFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSD 669 RVSN624 LQSSHFP 680 Y_PTM GTTYFN RFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSD 669RVSN 624 LQSSHFP 680 S_PTM GTTYFN RFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSE676 RVSN 624 LQSSHFP 680 Y_SW GTTYFN RFS WT CD3_SP11AVH3_VLK_3_RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 S_SW GTTYFN RFS WTCD3_SP11AVH3_VLK_3_ RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 Y_PTM_SW GTTYFNRFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 S_SWPTMGTTYFN RFS WT CD3_SP11AVH3_VLK_SW RSSQSLVRSD 669 RVSN 624 LQSSHFP 680PTM GTTYFN RFS WT CD3_SP11AVH3_VLK_3_ RSSQSLVRSE 676 RVSN 624 LQSSHFP680 SW GTTYFN RFS WT CD3_sp11a_VH1_VK2_Y RSSQSLVRSD 669 RVSN 624 LQSSHFP680 GTTYFN RFS WT CD3_sp11a_VH1_VK2_S RSSQSLVRSD 669 RVSN 624 LQSSHFP680 GTTYFN RFS WT CD3_sp11a_VH1_VK2_Y_ RSSQSLVRSE 676 RVSN 624 LQSSHFP680 PTM GTTYFN RFS WT CD3_sp11a_VH1_VK2_S_ RSSQSLVRSE 676 RVSN 624LQSSHFP 680 PTM GTTYFN RFS WT CD3_sp11a_VH1_VK2_Y_ RSSQSLVRSD 669 RVSN624 LQSSHFP 680 SW GTTYFN RFS WT CD3_sp11a_VH1_VK2_S_ RSSQSLVRSD 669RVSN 624 LQSSHFP 680 SW GTTYFN RFS WT CD3_sp11a_VH1_VK2_Y_ RSSQSLVRSE676 RVSN 624 LQSSHFP 680 PTM GTTYFN RFS WT CD3_sp11a_VH1_VK2_S_RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 PTM_SW GTTYFN RFS WTCD3_sp11a_VH1_VK2_S RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 W GTTYFN RFS WTCD3_sp11a_VH1_VK2_S RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 W_PTM GTTYFN RFSWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 Y GTTYFN RFSWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 S GTTYFN RFSWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 Y_PTM GTTYFNRFS WT CD3_SP11A_VH3_VLK1_ RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 S_PTMGTTYFN RFS WT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSN 624 LQSSHFP 680Y_SW GTTYFN RFS WT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSN 624 LQSSHFP680 S_SW GTTYFN RFS WT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSN 624LQSSHFP 680 Y_PTM GTTYFN RFS WT CD3_SP11A_VH3_VLK1_ RSSQSLVRSD 669 RVSN624 LQSSHFP 680 S_PTM_SW GTTYFN RFS WT CD3_SP11 A_VH3_VLK1P RSSQSLVRSD669 RVSN 624 LQSSHFP 680 TM_SW GTTYFN RFS WT CD3_SP11A_VH3_VLK1_RSSQSLVRSE 676 RVSN 624 LQSSHFP 680 SW GTTYFN RFS WT CD3_SP11A_VH5_VK2_YRSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WT CD3_SP11A_VH5_VK2_SRSSQSLVRSD 669 RVSN 624 LQSSHFP 680 GTTYFN RFS WT CD3_SP11A_VH5_VK2_YRSSQSLVRSD 669 RVSN 624 LQSSHFP 680 _PTM GTTYFN RFS WTCD3_SP11A_VH5_VK2_S RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 _PTM GTTYFN RFSWT CD3_SP11A_VH5_VK2_Y RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 _SW GTTYFNRFS WT CD3_SP11A_VH5_VK2_S RSSQSLVRSD 669 RVSN 624 LQSSHFP 680 _SWGTTYFN RFS WT CD3_SP11A_VH5_VK2_Y RSSQSLVRSD 669 RVSN 624 LQSSHFP 680_PTM_SW GTTYFN RFS WT CD3_SP11A_VH5_VK2_S RSSQSLVRSD 669 RVSN 624LQSSHFP 680 _PTM_SW GTTYFN RFS WT CD3_SP11A_VH5_VK2_P RSSQSLVRSD 669RVSN 624 LQSSHFP 680 TM_SW GTTYFN RFS WT CD3_SP11A_VH5_VK2_S RSSQSLVRSD669 RVSN 624 LQSSHFP 680 W GTTYFN RFS WT

TABLE AH-1 CD3 Binders- Heavy Chain CDR sequences according to combination of Kabat and IMGT numbering schemes SEQ ID SEQ ID SEQ IDBinder CDR-H1  NO: CDR-H2 NO: CDR-H3 NO: NOV292 GFTFSK 756 MIYYDSSKMY634 ASFWWDLDF 715 NGMH YADTVKG DH NOV123 GYTFTS 613 YIYPGHDAIYY 635VRPNTMMAPL 716 YYIY SENFKG AY Sp10b GYTFTS 613 YIYPGHDAIYY 635VRPNTMMAPL 716 YYIY SENFKG AY NOV453 GFSLTT 757 RMRYSGDTSF 636TSDPMYIPNY 717 YNVH NAALTS SYGVMNA NOV229 GFSLTT 757 RMRYSGDTSF 636ARDPMYIPNY 718 YNVH NAALTS SYGVMNA NOV110 GYTFTS 613 YIYPANGGIYY 637ARPVTMMAPL 719 YYIY SEKFKG VF NOV832 GYTFTS 613 YIYPANGGIYY 637ARPVTMMAPL 719 YYIY SEKFKG VF NOV589 GFTFSK 756 MIYYDSSRMY 638 ASFWWDLDF720 NGMH YADTVKG DY NOV580 GFSLTT 758 RMRYSGDTS 639 TRDPMYIPGY 721 YNIHYSSALKS SYGVMNA NOV567 GFAFRK 759 LIYYDSSKMN 640 AALNSEYD 582 YGMSYADTVKG NOV221 GFSLTT 758 RMRYSGDTS 639 TRDPMYIPGY 721 YNIH YSSALKSSYGVMNA CD3_sp11a_bkm1 GFTFSK 756 MIYYDSSKMY 634 ASFWWDLDF 715 NGMHYADTVKG DH CD3_SP11a_bkm2 GFTFSK 756 MIYYDSSKMY 634 AKFWWDLDF 722 NGMHYADTVKG DH CD3_sp11a_hz0 GFTFSK 756 MIYYDSSKMY 634 AKFWWDLDF 722 NGMHYADTVKG DH CD3_SP11A_HZ1 GFTFSK 756 MIYYDSSKMY 634 ASFWWDLDF 715 NGMHYADTVKG DH CD3_sp11a_sansPTM GFTFSK 760 MIYYDSSKMY 634 ASFWWDLDF 715_hz1 QGMH YADTVKG DH CD3_sp11a_sansPTM GFTFSK 760 MIYYDSSKMY 634ASFWWDLDF 715 _rat QGMH YADTVKG DH CD3_sp11a_VHVL_YY GFTFSK 756MIYYDSSKMY 634 ASFYYDLDFD 723 NGMH YADTVKG H CD3_SP11A_VHVL_S GFTFSK 756MIYYDSSKMY 634 ASFSSDLDFD 724 S NGMH YADTVKG H CD3_SP11A_VHVL_W GFTFSK756 MIYYDSSKMY 634 ASFWSDLDFD 725 S NGMH YADTVKG H CD3_sp11a_VHVL_SGFTFSK 756 MIYYDSSKMY 634 ASFSWDLDFD 726 W NGMH YADTVKG HCD3_SP11A_VHVL_T GFTFSK 756 MIYYDSSKMY 634 ASFTTDLDFD 727 T NGMH YADTVKGH CD3_SP11A_VHVL_T GFTFSK 756 MIYYDSSKMY 634 ASFTWDLDFD 728 W NGMHYADTVKG H CD3_SP11A_VHVL_W GFTFSK 756 MIYYDSSKMY 634 ASFWTDLDFD 729 TNGMH YADTVKG H CD3_SP11A GFTFSK 756 MIYYDSSKMY 634 ASFWWDLDF 715VH3_VLK_3 NGMH YADTVKG DH CD3_sp11a_VH1_VK2 GFTFSK 760 MIYYDSSKMY 634ASFWWDLDF 715 QGMH YADTVKG DH CD3_SP11A_VH3_VL GFTFSK 756 MIYYDSSKMY 634ASFWWDLDF 715 K1 NGMH YADTVKG DH CD3_SP11A_VH5_VK GFTFSK 760 MIYYDSSKMY634 ASFWWDLDF 715 2 QGMH YADTVKG DH CD3_sp9aFW1_VL_V GFSLTT 757RMRYSGDTSF 636 ASDPMYIPNY 730 H_S56G YNVH NAALTS AYGVMNACD3_SP9AFW4_VL_V GFSLTT 757 RMRYSGDTSF 636 ASDPMYIPNY 730 H_S56G YNVHNAALTS AYGVMNA CD3_sp9aFW1_VLVH GFSLTT 757 RMRYSGDTSF 636 ASDPMYIPNY 730YNVH NAALTS AYGVMNA CD3_sp9aFW4_VLVH GFSLTT 757 RMRYSGDTSF 636ASDPMYIPNY 730 YNVH NAALTS AYGVMNA CD3_sp9arabtor_VHVL GFSLTT 757RMRYSGDTSF 636 ASDPMYIPNY 730 YNVH NAALTS AYGVMNA CD3_sp9arabtor_VLVHGFSLTT 757 RMRYSGDTSF 636 ASDPMYIPNY 730 YNVH NAALTS AYGVMNACD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634 ASYWWDLDF 743 _3_Y NGMHYADTVKG DH CD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634 ASSWWDLDF 744 _3_SNGMH YADTVKG DH CD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634 ASYVWVDLDF743 _3_Y_PTM NGMH YADTVKG DH CD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634ASSWWDLDF 744 _3_S_PTM NGMH YADTVKG DH CD3_SP11AVH3_VLK GFTFSK 756MIYYDSSKMY 634 ASYSWDLDFD 737 _3_Y_SW NGMH YADTVKG H CD3_SP11AVH3_VLKGFTFSK 756 MIYYDSSKMY 634 ASSSWDLDFD 738 _3_S_SW NGMH YADTVKG HCD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634 ASYSWDLDFD 737 _3_Y_PTM_SWNGMH YADTVKG H CD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634 ASSSWDLDFD 738_3_S_SWPTM NGMH YADTVKG H CD3_SP11AVH3_VLK GFTFSK 756 MIYYDSSKMY 634ASFSWDLDFD 726 _SWPTM NGMH YADTVKG H CD3_SP11AVH3_VLK GFTFSK 756MIYYDSSKMY 634 ASFSWDLDFD 726 _3_SW NGMH YADTVKG H CD3_sp11a_VH1_VK2GFTFSK 760 MIYYDSSKMY 634 ASYWWDLDF 743 _Y QGMH YADTVKG DHCD3_sp11a_VH1_VK2 GFTFSK 760 MIYYDSSKMY 634 ASSWWDLDF 744 _S QGMHYADTVKG DH CD3_sp11a_VH1_VK2 GFTFSK 756 MIYYDSSKMY 634 ASYWWDLDF 743_Y_PTM NGMH YADTVKG DH CD3_sp11a_VH1_VK2 GFTFSK 756 MIYYDSSKMY 634ASSWWDLDF 744 _S_PTM NGMH YADTVKG DH CD3_sp11a_VH1_VK2 GFTFSK 760MIYYDSSKMY 634 ASYSWDLDFD 737 _Y_SW QGMH YADTVKG H CD3_sp11a_VH1_VK2GFTFSK 760 MIYYDSSKMY 634 ASSSWDLDFD 738 _S_SW QGMH YADTVKG HCD3_sp11a_VH1_VK2 GFTFSK 756 MIYYDSSKMY 634 ASYSWDLDFD 737 _Y_PTM NGMHYADTVKG H CD3_sp11a_VH1_VK2 GFTFSK 756 MIYYDSSKMY 634 ASSSWDLDFD 738_S_PTM_SW NGMH YADTVKG H CD3_sp11a_VH1_VK2 GFTFSK 760 MIYYDSSKMY 634ASFSWDLDFD 726 _SW QGMH YADTVKG H CD3_sp11a_VH1_VK2 GFTFSK 756MIYYDSSKMY 634 ASFSWDLDFD 726 _SW_PTM NGMH YADTVKG H CD3_SP11A_VH3_VLGFTFSK 756 MIYYDSSKMY 634 ASYVWVDLDF 743 K1_Y NGMH YADTVKG DHCD3_SP11A_VH3_VL GFTFSK 756 MIYYDSSKMY 634 ASSWWDLDF 744 K1_S NGMHYADTVKG DH CD3_SP11A_VH3_VL GFTFSK 760 MIYYDSSKMY 634 ASYVWVDLDF 743K1_Y_PTM QGMH YADTVKG DH CD3_SP11A_VH3_VL GFTFSK 760 MIYYDSSKMY 634ASSWWDLDF 744 K1_S_PTM QGMH YADTVKG DH CD3_SP11A_VH3_VL GFTFSK 756MIYYDSSKMY 634 ASYSWDLDFD 737 K1_Y_SW NGMH YADTVKG H CD3_SP11A_VH3_VLGFTFSK 756 MIYYDSSKMY 634 ASSSWDLDFD 738 K1_S_SW NGMH YADTVKG HCD3_SP11A_VH3_VL GFTFSK 760 MIYYDSSKMY 634 ASYVWVDLDF 743 K1_Y_PTM QGMHYADTVKG DH CD3_SP11A_VH3_VL GFTFSK 760 MIYYDSSKMY 634 ASSSWDLDFD 738K1_S_PTM_SW QGMH YADTVKG H CD3_SP11A_VH3_VL GFTFSK 760 MIYYDSSKMY 634ASFSWDLDFD 726 K1PTM_SW QGMH YADTVKG H CD3_SP11A_VH3_VL GFTFSK 756MIYYDSSKMY 634 ASFSWDLDFD 726 K1_SW NGMH YADTVKG H CD3_SP11A_VH5_VKGFTFSK 760 MIYYDSSKMY 634 ASYVWVDLDF 743 2_Y QGMH YADTVKG DHCD3_SP11A_VH5_VK GFTFSK 760 MIYYDSSKMY 634 ASSWWDLDF 744 2_S QGMHYADTVKG DH CD3_SP11A_VH5_VK GFTFSK 756 MIYYDSSKMY 634 ASYVWVDLDF 7432_Y_PTM NGMH YADTVKG DH CD3_SP11A_VH5_VK GFTFSK 756 MIYYDSSKMY 634ASSWWDLDF 744 2_S_PTM NGMH YADTVKG DH CD3_SP11A_VH5_VK GFTFSK 760MIYYDSSKMY 634 ASYSWDLDFD 737 2_Y_SW QGMH YADTVKG H CD3_SP11A_VH5_VKGFTFSK 760 MIYYDSSKMY 634 ASSSWDLDFD 738 2_S_SW QGMH YADTVKG HCD3_SP11A_VH5_VK GFTFSK 756 MIYYDSSKMY 634 ASYSWDLDFD 737 2_Y_PTM_SWNGMH YADTVKG H CD3_SP11A_VH5_VK GFTFSK 756 MIYYDSSKMY 634 ASSSWDLDFD 7382_S_PTM_SW NGMH YADTVKG H CD3_SP11A_VH5_VK GFTFSK 756 MIYYDSSKMY 634ASFSWDLDFD 726 2_PTM_SW NGMH YADTVKG H CD3_SP11A_VH5_VK GFTFSK 760MIYYDSSKMY 634 ASFSWDLDFD 726 2_SW QGMH YADTVKG H

TABLE AH-2CD3 Binders-Light Chain CDR sequences according to combination of Kabat and IMGTnumbering schemes SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2 NO:CDR-L3 NO: NOV292 RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTNOV123 RSSQSLIYSIG 670 RVSNRF 624 FQSTHL 626 NTYLH S PYT Sp10bRSSQSLIYSIG 670 RVSNRF 624 FQSTHL 626 NTYLH S PYT NOV453 KASQNINNYLN 671NTDHLQ 753 LQHRSR 681 AGVP YT NOV229 KASQNINNYLN 671 NTDHLQ 753 LQHRSR681 AGVP YT NOV110 RSSQSLVYSH 672 RVSNRF 624 FQSTHL 626 GNTYLH S PYTNOV832 RSSQSLVYSH 672 RVSNRF 624 FQSTHL 626 GNTYLH S PYT NOV589RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWT NOV580 KTSQNIDKYLN 673NTNNLE 754 LQHRSS 682 AGVP YT NOV567 RGSQSIGNSL 674 STSTLEY 755 LQYATY683 N GVP PYT NOV221 KSSQNIDKYLN 675 NTNNLE 754 LQHRS 684 AGVP GYTCD3_sp11a_bkm1 RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11a_bkm2 RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_sp11a_hz0 RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_HZ1 RSSQSLVRSD 669 RVSNRF 624 LQSSH 685 GTTYFN SCD3_sp11a_sansPTM_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 hz1 GTTYFN S PWTCD3_sp11a_sansPTM_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 rat GTTYFN S PWTCD3_sp11a_VHVL_YY RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VHVL_SS RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VHVL_WS RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_sp11a_VHVL_SW RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VHVL_TT RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VHVL_TW RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VHVL_WT RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VH3_VLK_3 RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_sp11a_VH1_VK2 RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VH3_VLK1 RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_SP11A_VH5_VK2 RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_sp9aFW1_VL_VH_ KASQNINNYLN 671 NTDHLQ 753 LQHRSR 681 S56G AGVP YTCD3_SP9AFW4_VL_VH_ KASQNINNYLN 671 NTDHLQ 753 LQHRSR 681 S56G AGVP YTCD3_sp9aFW1_VLVH KASQNINNYLN 671 NTDHLQ 753 LQHRSR 681 AGVP YTCD3_sp9aFW4_VLVH KASQNINNYLN 671 NTDHLQ 753 LQHRSR 681 AGVP YTCD3_sp9arabtor_VHVL KASQNINNYLN 671 NTDHLQ 753 LQHRSR 681 AGVP YTCD3_sp9arabtor_VLVH KASQNINNYLN 671 NTDHLQ 753 LQHRSR 681 AGVP YTCD3_SP11AVH3_VLK_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 3_Y GTTYFN S PWTCD3_SP11AVH3_VLK_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 3_S GTTYFN S PWTCD3_SP11AVH3_VLK_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 3_Y_PTM GTTYFN SPWT CD3_SP11AVH3_VLK_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 3_S_PTMGTTYFN S PWT CD3_SP11AVH3_VLK_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 6803_Y_SW GTTYFN S PWT CD3_SP11AVH3_VLK_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF680 3_S_SW GTTYFN S PWT CD3_SP11AVH3_VLK_ RSSQSLVRSD 669 RVSNRF 624LQSSHF 680 3_Y_PTM_SW GTTYFN S PWT CD3_SP11AVH3_VLK_ RSSQSLVRSD 669RVSNRF 624 LQSSHF 680 3_S_SWPTM GTTYFN S PWT CD3_SP11AVH3_VLK_RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 SWPTM GTTYFN S PWTCD3_SP11AVH3_VLK_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 3_SW GTTYFN S PWTCD3_sp11a_VH1_VK2_Y RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_sp11a_VH1_VK2_S RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 GTTYFN S PWTCD3_sp11a_VH1_VK2_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 Y_PTM GTTYFN SPWT CD3_sp11a_VH1_VK2_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 S_PTM GTTYFNS PWT CD3_sp11a_VH1_VK2_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 Y_SWGTTYFN S PWT CD3_sp11a_VH1_VK2_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680S_SW GTTYFN S PWT CD3_sp11a_VH1_VK2_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF680 Y_PTM GTTYFN S PWT CD3_sp11a_VH1_VK2_ RSSQSLVRSE 676 RVSNRF 624LQSSHF 680 S_PTM_SW GTTYFN S PWT CD3_sp11a_VH1_VK2_ RSSQSLVRSD 669RVSNRF 624 LQSSHF 680 SW GTTYFN S PWT CD3_sp11a_VH1_VK2_ RSSQSLVRSE 676RVSNRF 624 LQSSHF 680 SW_PTM GTTYFN S PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE676 RVSNRF 624 LQSSHF 680 Y GTTYFN S PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE676 RVSNRF 624 LQSSHF 680 S GTTYFN S PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSD669 RVSNRF 624 LQSSHF 680 Y_PTM GTTYFN S PWT CD3_SP11A_VH3_VLK1_RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 S_PTM GTTYFN S PWTCD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 Y_SW GTTYFN SPWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSNRF 624 LQSSHF 680 S_SW GTTYFNS PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 Y_PTMGTTYFN S PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680S_PTM_SW GTTYFN S PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSD 669 RVSNRF 624LQSSHF 680 PTM_SW GTTYFN S PWT CD3_SP11A_VH3_VLK1_ RSSQSLVRSE 676 RVSNRF624 LQSSHF 680 SW GTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF624 LQSSHF 680 Y GTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF624 LQSSHF 680 S GTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF624 LQSSHF 680 Y_PTM GTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669RVSNRF 624 LQSSHF 680 S_PTM GTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD669 RVSNRF 624 LQSSHF 680 Y_SW GTTYFN S PWT CD3_SP11A_VH5_VK2_RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 S_SW GTTYFN S PWTCD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 Y_PTM_SW GTTYFNS PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680 S_PTM_SWGTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF 680PTM_SW GTTYFN S PWT CD3_SP11A_VH5_VK2_ RSSQSLVRSD 669 RVSNRF 624 LQSSHF680 SW GTTYFN S PWT

TABLE AI-1CD3 Binders-Heavy Chain CDR sequences according to combination of Chothia and IMGTnumbering schemes SEQ ID SEQ ID SEQ ID Binder CDR-H1 NO: CDR-H2 NO:CDR-H3 NO: NOV292 GFTFS 708 YYDS 689 ASFWWDLDFDH 715 KNG SK NOV123 GYTFT614 YPGH 690 VRPNTMMAPLA 716 SYY DA Y Sp10b GYTFT 614 YPGH 690VRPNTMMAPLA 716 SYY DA Y NOV453 GFSLTT 597 RYSG 601 TSDPMYIPNYSY 717 YND GVMNA NOV229 GFSLTT 597 RYSG 601 ARDPMYIPNYSY 718 YN D GVMNA NOV110GYTFT 614 YPAN 691 ARPVTMMAPLVF 719 SYY GG NOV832 GYTFT 614 YPAN 691ARPVTMMAPLVF 719 SYY GG NOV589 GFTFS 708 YYDS 692 ASFWWDLDFDY 720 KNG SRNOV580 GFSLTT 597 RYSG 601 TRDPMYIPGYSY 721 YN D GVMNA NOV567 GFAFR 709YYDS 689 AALNSEYD 582 KYG SK NOV221 GFSLTT 597 RYSG 601 TRDPMYIPGYSY 721YN D GVMNA CD3_sp11a_bkm1 GFTFS 708 YYDS 689 ASFWWDLDFDH 715 KNG SKCD3_SP11a_bkm2 GFTFS 708 YYDS 689 AKFWWDLDFDH 722 KNG SK CD3_sp11a_hz0GFTFS 708 YYDS 689 AKFWWDLDFDH 722 KNG SK CD3_SP11A_HZ1 GFTFS 708 YYDS689 ASFWWDLDFDH 715 KNG SK CD3_sp11a_sansPTM_ GFTFS 710 YYDS 689ASFWWDLDFDH 715 hz1 KQG SK CD3_sp11a_sansPTM_ GFTFS 710 YYDS 689ASFWWDLDFDH 715 rat KQG SK CD3_sp11a_VHVL_YY GFTFS 708 YYDS 689ASFYYDLDFDH 723 KNG SK CD3_SP11A_VHVL_SS GFTFS 708 YYDS 689 ASFSSDLDFDH724 KNG SK CD3_SP11A_VHVL_WS GFTFS 708 YYDS 689 ASFWSDLDFDH 725 KNG SKCD3_sp11a_VHVL_SW GFTFS 708 YYDS 689 ASFSWDLDFDH 726 KNG SKCD3_SP11A_VHVL_TT GFTFS 708 YYDS 689 ASFTTDLDFDH 727 KNG SKCD3_SP11A_VHVL_TW GFTFS 708 YYDS 689 ASFTWDLDFDH 728 KNG SKCD3_SP11A_VHVL_WT GFTFS 708 YYDS 689 ASFWTDLDFDH 729 KNG SKCD3_SP11A_VH3_VLK_3 GFTFS 708 YYDS 689 ASFWWDLDFDH 715 KNG SKCD3_sp11a_VH1_VK2 GFTFS 710 YYDS 689 ASFWWDLDFDH 715 KQG SKCD3_SP11A_VH3_VLK1 GFTFS 708 YYDS 689 ASFWWDLDFDH 715 KNG SKCD3_SP11A_VH5_VK2 GFTFS 710 YYDS 689 ASFWWDLDFDH 715 KQG SKCD3_sp9aFW1_VL_VH_ GFSLTT 597 RYSG 601 ASDPMYIPNYAY 730 S56G YN D GVMNACD3_SP9AFW4_VL_VH_ GFSLTT 597 RYSG 601 ASDPMYIPNYAY 730 S56G YN D GVMNACD3_sp9aFW1_VLVH GFSLTT 597 RYSG 601 ASDPMYIPNYAY 730 YN D GVMNACD3_sp9aFW4_VLVH GFSLTT 597 RYSG 601 ASDPMYIPNYAY 730 YN D GVMNACD3_sp9arabtor_VHVL GFSLTT 597 RYSG 601 ASDPMYIPNYAY 730 YN D GVMNACD3_sp9arabtor_VLVH GFSLTT 597 RYSG 601 ASDPMYIPNYAY 730 YN D GVMNACD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASYWWDLDFDH 743 Y KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASSWWDLDFDH 744 S KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASYWWDLDFDH 743 Y_PTM KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASSWWDLDFDH 744 S_PTM KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASYSWDLDFDH 737 Y_SW KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASSSWDLDFDH 738 S_SW KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASYSWDLDFDH 737 Y_PTM_SW KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASSSWDLDFDH 738 S_SWPTM KNG SKCD3_SP11AVH3_VLK_S GFTFS 708 YYDS 689 ASFSWDLDFDH 726 WPTM KNG SKCD3_SP11AVH3_VLK_3_ GFTFS 708 YYDS 689 ASFSWDLDFDH 726 SW KNG SKCD3_sp11a_VH1_VK2_Y GFTFS 710 YYDS 689 ASYWWDLDFDH 743 KQG SKCD3_sp11a_VH1_VK2_S GFTFS 710 YYDS 689 ASSWWDLDFDH 744 KQG SKCD3_sp11a_VH1_VK2_Y_ GFTFS 708 YYDS 689 ASYWWDLDFDH 743 PTM KNG SKCD3_sp11a_VH1_VK2_S_ GFTFS 708 YYDS 689 ASSWWDLDFDH 744 PTM KNG SKCD3_sp11a_VH1_VK2_Y_ GFTFS 710 YYDS 689 ASYSWDLDFDH 737 sw KQG SKCD3_sp11a_VH1_VK2_S_ GFTFS 710 YYDS 689 ASSSWDLDFDH 738 SW KQG SKCD3_sp11a_VH1_VK2_Y_ GFTFS 708 YYDS 689 ASYSWDLDFDH 737 PTM KNG SKCD3_sp11a_VH1_VK2_S_ GFTFS 708 YYDS 689 ASSSWDLDFDH 738 PTM_SW KNG SKCD3_sp11a_VH1_VK2_ GFTFS 710 YYDS 689 ASFSWDLDFDH 726 SW KQG SKCD3_sp11a_VH1_VK2_ GFTFS 708 YYDS 689 ASFSWDLDFDH 726 SW_PTM KNG SKCD3_SP11A_VH3_VLK1_ GFTFS 708 YYDS 689 ASYWWDLDFDH 743 Y KNG SKCD3_SP11A_VH3_VLK1_ GFTFS 708 YYDS 689 ASSWWDLDFDH 744 S KNG SKCD3_SP11A_VH3_VLK1_ GFTFS 710 YYDS 689 ASYWWDLDFDH 743 Y_PTM KQG SKCD3_SP11A_VH3_VLK1_ GFTFS 710 YYDS 689 ASSWWDLDFDH 744 S_PTM KQG SKCD3_SP11A_VH3_VLK1_ GFTFS 708 YYDS 689 ASYSWDLDFDH 737 Y_SW KNG SKCD3_SP11A_VH3_VLK1_ GFTFS 708 YYDS 689 ASSSWDLDFDH 738 S_SW KNG SKCD3_SP11A_VH3_VLK1_ GFTFS 710 YYDS 689 ASYWWDLDFDH 743 Y_PTM KQG SKCD3_SP11A_VH3_VLK1_ GFTFS 710 YYDS 689 ASSSWDLDFDH 738 S_PTM_SW KQG SKCD3_SP11A_VH3_VLK1_ GFTFS 710 YYDS 689 ASFSWDLDFDH 726 PTM_SW KQG SKCD3_SP11A_VH3_VLK1_ GFTFS 708 YYDS 689 ASFSWDLDFDH 726 SW KNG SKCD3_SP11A_VH5_VK2_Y GFTFS 710 YYDS 689 ASYWWDLDFDH 743 KQG SKCD3_SP11A_VH5_VK2_S GFTFS 710 YYDS 689 ASSWWDLDFDH 744 KQG SKCD3_SP11A_VH5_VK2_ GFTFS 708 YYDS 689 ASYWWDLDFDH 743 Y_PTM KNG SKCD3_SP11A_VH5_VK2_ GFTFS 708 YYDS 689 ASSWWDLDFDH 744 S_PTM KNG SKCD3_SP11A_VH5_VK2_ GFTFS 710 YYDS 689 ASYSWDLDFDH 737 Y_SW KQG SKCD3_SP11A_VH5_VK2_ GFTFS 710 YYDS 689 ASSSWDLDFDH 738 S_SW KQG SKCD3_SP11A_VH5_VK2_ GFTFS 708 YYDS 689 ASYSWDLDFDH 737 Y_PTM_SW KNG SKCD3_SP11A_VH5_VK2_ GFTFS 708 YYDS 689 ASSSWDLDFDH 738 S_PTM_SW KNG SKCD3_SP11A_VH5_VK2_ GFTFS 708 YYDS 689 ASFSWDLDFDH 726 PTM_SW KNG SKCD3_SP11A_VH5_VK2_ GFTFS 710 YYDS 689 ASFSWDLDFDH 726 SW KQG SK

TABLE AI-2CD3 Binders-Light Chain CDR sequences according to combination of Chothia and IMGTnumbering schemes SEQ ID SEQ ID SEQ ID Binder CDR-L1 NO: CDR-L2 NO:CDR-L3 NO: NOV292 SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWT NOV123SQSLIYSIG 694 RVS 625 FQSTHL 626 NTY PYT Sp10b SQSLIYSIG 694 RVS 625FQSTHL 626 NTY PYT NOV453 SQNINNY 695 NTDHLQA 753 LQHRSR 681 GVP YTNOV229 SQNINNY 695 NTDHLQA 753 LQHRSR 681 GVP YT NOV110 SQSLVYSH 696 RVS625 FQSTHL 626 GNTY PYT NOV832 SQSLVYSH 696 RVS 625 FQSTHL 626 GNTY PYTNOV589 SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWT NOV580 SQNIDKY 697NTNNLEA 754 LQHRSS 682 GVP YT NOV567 SQSIGNS 698 STSTLEY 755 LQYATY 683GVP PYT NOV221 SQNIDKY 697 NTNNLEA 754 LQHRSG 684 GVP YT CD3_sp11a_bkm1SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWT CD3_SP11a_bkm2 SQSLVRSD 693 RVS625 LQSSHF 680 GTTY PWT CD3_sp11a_hz0 SQSLVRSD 693 RVS 625 LQSSHF 680GTTY PWT CD3_SP11A_HZ1 SQSLVRSD 693 RVS 625 LQSSHF 761 GTTY PWCD3_sp11a_sansPTM_ SQSLVRSE 699 RVS 625 LQSSHF 680 hz1 GTTY PWTCD3_sp11a_sansPTM_ SQSLVRSE 699 RVS 625 LQSSHF 680 rat GTTY PWTCD3_sp11a_VHVL_YY SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_SS SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_WS SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VHVL_SW SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_TT SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_TW SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VHVL_WT SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK_3 SQSLVRSE 699 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2 SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH3_VLK1 SQSLVRSE 699 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2 SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_sp9aFW1_VL_VH_ SQNINNY 695 NTDHLQA 753 LQHRSR 681 S56G GVP YTCD3_SP9AFW4_VL_VH_ SQNINNY 695 NTDHLQA 753 LQHRSR 681 S56G GVP YTCD3_sp9aFW1_VLVH SQNINNY 695 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9aFW4_VLVH SQNINNY 695 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9arabtor_VHVL SQNINNY 695 NTDHLQA 753 LQHRSR 681 GVP YTCD3_sp9arabtor_VLVH SQNINNY 695 NTDHLQA 753 LQHRSR 681 GVP YTCD3_SP11AVH3_VLK_3_ SQSLVRSE 699 RVS 625 LQSSHF 680 Y GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSE 699 RVS 625 LQSSHF 680 S GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_PTM GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_PTM GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSE 699 RVS 625 LQSSHF 680 Y_SW GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSE 699 RVS 625 LQSSHF 680 S_SW GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_PTM_SW GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_SWPTM GTTY PWTCD3_SP11AVH3_VLK_ SQSLVRSD 693 RVS 625 LQSSHF 680 SWPTM GTTY PWTCD3_SP11AVH3_VLK_3_ SQSLVRSE 699 RVS 625 LQSSHF 680 SW GTTY PWTCD3_sp11a_VH1_VK2_Y SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_S SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_sp11a_VH1_VK2_Y_ SQSLVRSE 699 RVS 625 LQSSHF 680 PTM GTTY PWTCD3_sp11a_VH1_VK2_S_ SQSLVRSE 699 RVS 625 LQSSHF 680 PTM GTTY PWTCD3_sp11a_VH1_VK2_Y_ SQSLVRSD 693 RVS 625 LQSSHF 680 SW GTTY PWTCD3_sp11a_VH1_VK2_S_ SQSLVRSD 693 RVS 625 LQSSHF 680 SW GTTY PWTCD3_sp11a_VH1_VK2_Y_ SQSLVRSE 699 RVS 625 LQSSHF 680 PTM GTTY PWTCD3_sp11a_VH1_VK2_S_ SQSLVRSE 699 RVS 625 LQSSHF 680 PTM_SW GTTY PWTCD3_sp11a_VH1_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 SW GTTY PWTCD3_sp11a_VH1_VK2_ SQSLVRSE 699 RVS 625 LQSSHF 680 SW_PTM GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSE 699 RVS 625 LQSSHF 680 Y GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSE 699 RVS 625 LQSSHF 680 S GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_PTM GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_PTM GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSE 699 RVS 625 LQSSHF 680 Y_SW GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSE 699 RVS 625 LQSSHF 680 S_SW GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_PTM GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_PTM_SW GTTY PWTCD3_SP11A_VH3_VLK1P SQSLVRSD 693 RVS 625 LQSSHF 680 TM_SW GTTY PWTCD3_SP11A_VH3_VLK1_ SQSLVRSE 699 RVS 625 LQSSHF 680 SW GTTY PWTCD3_SP11A_VH5_VK2_Y SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_S SQSLVRSD 693 RVS 625 LQSSHF 680 GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_PTM GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_PTM GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_SW GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_SW GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 Y_PTM_SW GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 S_PTM_SW GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 PTM_SW GTTY PWTCD3_SP11A_VH5_VK2_ SQSLVRSD 693 RVS 625 LQSSHF 680 SW GTTY PWT

TABLE AJ-1 CD3 Binders-Heavy chain variable sequences SEQ ID BinderSequence NO: NOV292 QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 762PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFVWVDLDFDHWGQGTMVTVSS NOV123QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIYWVRQAPG 763QRLEWMGYIYPGHDAIYYSENFKGRVTITADTSASTAYMELSSLRSEDTAVYYCVRPNTMMAPLAYWGQGTLVTVSS Sp10bQVQLHQSGAELAKPGTSVNLSCKASGYTFTSYYIYWIKRRPG 764QGLEWIGYIYPGHDAIYYSENFKGKATFTADTSSSTAYMLLGSLTPEDSAYYFCVRPNTMMAPLAYWGQGTLVTVSS NOV453QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYNVHWIRQPPG 765KGLEWIGRMRYSGDTSFNAALTSRVTISRDTSKNQVSLKLSSVTAADTAVYYCTSDPMYIPNYSYGVMNAWGQGTTVTVSS NOV229QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYNVHWIRQPPG 766KGLEWIGRMRYSGDTSFNAALTSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDPMYIPNYSYGVMNAWGQGTTVTVSS NOV110QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIYWVRQAPG 767QRLEWMGYIYPANGGIYYSEKFKGRVTITADTSAGTAYMELSSLRSEDTAVYYCARPVTMMAPLVFWGQGTLVTVSS NOV832QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIYWVRQAPG 768QRLEWMGYIYPANGGIYYSEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARPVTMMAPLVFWGQGTLVTVSS NOV589QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 769PGKGLEWVAMIYYDSSRMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWWDLDFDYWGQGTMVTVSS NOV580QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYNIHWIRQPPGK 770GLEWIGRMRYSGDTSYSSALKSRVTISRDTSKNQVSLKLSSVTAADTAVYYCTRDPMYIPGYSYGVMNAWGQGTTVTVSS NOV567QVQLVESGGGVVQPGRSLRLSCAASGFAFRKYGMSWVRQA 771PGKGLEWVALIYYDSSKMNYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAALNSEYDWGQGTMVTVSS NOV221QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYNIHWIRQPPGK 770GLEWIGRMRYSGDTSYSSALKSRVTISRDTSKNQVSLKLSSVTAADTAVYYCTRDPMYIPGYSYGVMNAWGQGTTVTVSS CD3_sp11a_bkm1QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 762PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWWDLDFDHWGQGTMVTVSS CD3_SP11a_bkm2QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 772PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKFWWDLDFDHWGQGTMVTVSS CD3_sp11a_hz0QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 772PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKFWWDLDFDHWGQGTMVTVSS CD3_SP11A_HZ1QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 762PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFVWVDLDFDHWGQGTMVTVSS CD3_sp11a_sansPTM_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 773 hz1PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFVWVDLDFDHWGQGTMVTVSS CD3_sp11a_sansPTM_EVKLVESGGDLVQPGDSLTLSCVASGFTFSKQGMHWIRQAPK 774 ratKGLEWIAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCASFVWVDLDFDHWGQGVMVTVSS CD3_sp11a_VHVL_YYQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 775PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFYYDLDFDHWGQGTMVTVSS CD3_SP11A_VHVL_SSQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 776PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSSDLDFDHWGQGTMVTVSS CD3_SP11A_VHVL_WSQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 777PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SWQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 778PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_SP11A_VHVL_TTQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 779PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFTTDLDFDHWGQGTMVTVSS CD3_SP11A_VHVL_TWQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 780PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFTWDLDFDHWGQGTMVTVSS CD3_SP11A_VHVL_WTQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 781PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWTDLDFDHWGQGTMVTVSS CD3_SP11A VH3_VLK_3QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 762PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 782PGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASFWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 762PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2EVQLVQSGAEVKKPGESLKISCKGSGFTFSKQGMHWVRQMP 783GKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASFVWVDLDFDHWGQGTMVTVSS CD3_sp9aFW1_VL_VH_EVQLVESGGGLVQPGGSLRLSCAASGFSLTTYNVHWVRQAP 784 S56GGKGLEWVGRMRYSGDTSFNAALTSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASDPMYIPNYAYGVMNAWGQGTLVTVSS CD3_SP9AFW4_VL_VH_EVQLVETGGGLVQPGGSRRLSCAASGFSLTTYNVHWVRQAP 785 S56GGKGLEWVGRMRYSGDTSFNAALTSRFTISRDTSKNTVYLQMNSLRAEDTGVYYCASDPMYIPNYAYGVMNAWGQGTLVTVSS CD3_sp9aFW1_VLVHEVQLVETGGGLVQPGGSRRLSCAASGFSLTTYNVHWVRQAP 786GKGLEWVSRMRYSGDTSFNAALTSRFTISRDTSKNTVYLQMNSLRAEDTGVYYCASDPMYIPNYAYGVMNAWGQGTLVTVSS CD3_sp9aFW4_VLVHVQLVESGGGLVQPGGSLRLSCAASGFSLTTYNVHWVRQAPG 787KGLEWVSRMRYSGDTSFNAALTSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASDPMYIPNYAYGVMNAWGQGTLVTVSS CD3_sp9arabtor_VHVLEVQLVESGGGSVQPGGSLRLSCTASGFSLTTYNVHWVRQAP 788GKGLEWVGRMRYSGDTSFNAALTSRFTISRDTSKNTVYLQMNSLRAEDTATYYCASDPMYIPNYAYGVMNAWGQGTTVTVSS CD3_sp9arabtor_VLVHEVQLVESGGGSVQPGGSLRLSCTASGFSLTTYNVHWVRQAP 788GKGLEWVGRMRYSGDTSFNAALTSRFTISRDTSKNTVYLQMNSLRAEDTATYYCASDPMYIPNYAYGVMNAWGQGTTVTVSS CD3_sp11a_VHVL_YY_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 789 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFYYDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_YY_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 790 SANSPTM_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYYYDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_YY_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 791 SANSPTM_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSYYDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_YY_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 792 YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYYYDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_YY_sQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 793PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSYYDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 794 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 795 SANSPTM_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 796 SANSPTM_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 797 YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 798 SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 794 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_WS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 799 SANSPTM_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_WS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 800 SANSPTM_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_WS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 801 YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_WS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 802 SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_WS_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 803 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFWSDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 804 SANSPTM_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 805 SANSPTM_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 806 YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 807 SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_SW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 808 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 809 SANSPTM_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYTWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 810 SANSPTM_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSTWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 811 YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYTWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 812 SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSTWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TW_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 813 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFTWDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TT_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 814 SANSPTM_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYTTDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TT_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 815 SANSPTM_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSTTDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TT_YQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 816PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYTTDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TT_SQVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 817PGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSTTDLDFDHWGQGTMVTVSS CD3_sp11a_VHVL_TT_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 818 SANSPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFTTDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 819 3_YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 820 3_SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 819 3_Y_PTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 820 3_S_PTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 806 3_Y_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 807 3_S_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 806 3_Y_PTM_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 807 3_S_SWPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 778 SWPTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_SP11AVH3_VLK_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 778 3_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_YQVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 821PGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_SQVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 822PGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKNGMHWVRQAP 823 Y_PTMGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 824 S_PTMPGNGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 825 Y_SWPGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 826 S_SWPGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKNGMHWVRQAP 827 Y_PTMGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 828 S_PTM_SWPGNGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 829 SWPGQGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_sp11a_VH1_VK2_QVQLVQSGAEVKKPGASVKVSCKASGFTFSKQGMHWVRQA 830 SW_PTMPGNGLEWMGMIYYDSSKMYYADTVKGRVTMTRDTSTNTLYMELSSLRSEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 819 YPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 820 SPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 831 Y_PTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 832 S_PTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 806 Y_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 820 S_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 831 Y_PTMPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 805 S_PTM_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASSSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKQGMHWVRQA 808 PTM_SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH3_VLK1_QVQLVESGGGVVQPGRSLRLSCAASGFTFSKNGMHWVRQA 778 SWPGKGLEWVAMIYYDSSKMYYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASFSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKQGMHWVRQMP 833 YGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKQGMHWVRQMP 834 SGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASSWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKNGMHWVRQMP 835 Y_PTMGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASYWWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKNGMHWVRQMP 836 S_PTMGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASSVWVDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKQGMHWVRQMP 837 Y_SWGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASYSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKQGMHWVRQMP 838 S_SWGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASSSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKNGMHWVRQMP 839 Y_PTM_SWGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASYSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKNGMHWVRQMP 840 S_PTM_SWGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASSSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKNGMHWVRQMP 841 PTM_SWGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASFSWDLDFDHWGQGTMVTVSS CD3_SP11A_VH5_VK2_EVQLVQSGAEVKKPGESLKISCKGSGFTFSKQGMHWVRQMP 842 SWGKGLEWMGMIYYDSSKMYYADTVKGQVTISRDNSINTLYLQWSSLKASDTAMYYCASFSWDLDFDHWGQGTMVTVSS

TABLE AJ-2 CD3 Binders-Light chain variable sequences SEQ ID BinderSequence NO: NOV292 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKNOV123 DVVMTQSPLSLPVTLGQPASISCRSSQSLIYSIGNTYLHWYQQ 844RPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DVGVYYCFQSTHLPYTFGQGTKLEIKSp10b WVLTQTPVSLPVSLGGQASISCRSSQSLIYSIGNTYLHWYLQ 845KPGQSPQLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEPE DLGDYYCFQSTHLPYTFGAGTKLELKNOV453 DIQMTQSPSSLSASVGDRVTITCKASQNINNYLNWYQQKPGK 846APKLLIYNTDHLQAGVPSRFSGSGSGTDYTLTISSLQPEDFATY FCLQHRSRYTFGPGTKVDIK NOV229DIQMTQSPSSLSASVGDRVTITCKASQNINNYLNWYQQKPGK 847APKLLIYNTDHLQAGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCLQHRSRYTFGPGTKVDIK NOV110DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSHGNTYLHWYQ 848QRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEA EDVGVYYCFQSTHLPYTFGQGTKLEIKNOV832 DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSHGNTYLHWFQ 849QRPGQSPRRLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVE AEDVGVYYCFQSTHLPYTFGQGTKLEIKNOV589 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKNOV580 DIQMTQSPSSLSASVGDRVTITCKTSQNIDKYLNWYQQKPGK 850APKLLIYNTNNLEAGVPSRFSGSGSGTDYTFTISSLQPEDIATY FCLQHRSSYTFGQGTKLEIK NOV567DIQMTQSPSSLSASVGDRVTITCRGSQSIGNSLNWYQQKPGK 851APKRLIYSTSTLEYGVPSRFSGSGSGTEYTLTISSLQPEDFATY YCLQYATYPYTFGQGTKLEIKNOV221 DIQMTQSPSSLSASVGDRVTITCKSSQNIDKYLNWYQQKPGK 852APKLLIYNTNNLEAGVPSRFSGSGSGTDYTFTISSLQPEDIATY FCLQHRSGYTFGQGTKLEIKCD3_sp11a_bkm1 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWLQ 853QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11a_bkm2 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_hz0 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWLQ 853QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_HZ1 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 854QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHCD3_sp11a_sansPTM_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 hz1QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_sansPTM_ DILVTQTPVSLPVSLGGHVSISCRSSQSLVRSEGTTYFNWYLQ 856 ratKPGQSPQLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEPE DLGVYYCLQSSHFPWTFGGGTKLELKCD3_sp11a_VHVL_YY DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VHVL_SS DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VHVL_WS DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SW DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VHVL_TT DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VHVL_TW DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VHVL_WT DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A VH3_VLK_3 EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSEGTTYFNWYQ 857QKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1 DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSEGTTYFNWYQ 858QKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2 DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp9aFW1_VL_VH_ EIVMTQSPSTLSASVGDRVIITCKASQNINNYLNWYQQKPGKA 859 S56GPKLLIYNTDHLQAGVPSRFSGSGSGAEFTLTISSLQPDDFATYY CLQHRSRYTFGQGTKLTVLCD3_SP9AFW4_VL_VH_ EIVMTQSPSTLSASVGDRVIITCKASQNINNYLNWYQQKPGKA 859 S56GPKLLIYNTDHLQAGVPSRFSGSGSGAEFTLTISSLQPDDFATYY CLQHRSRYTFGQGTKLTVLCD3_sp9aFW1_VLVH EIVMTQSPSTLSASVGDRVIITCKASQNINNYLNWYQQKPGKA 859PKLLIYNTDHLQAGVPSRFSGSGSGAEFTLTISSLQPDDFATYY CLQHRSRYTFGQGTKLTVLCD3_sp9aFW4_VLVH EIVMTQSPSTLSASVGDRVIITCKASQNINNYLNWYQQKPGKA 859PKLLIYNTDHLQAGVPSRFSGSGSGAEFTLTISSLQPDDFATYY CLQHRSRYTFGQGTKLTVLCD3_sp9arabtor_VHVL EIVMTQSPSTLSASVGDRVIITCKASQNINNYLNWYQQKPGKA 859PKLLIYNTDHLQAGVPSRFSGSGSGAEFTLTISSLQPDDFATYY CLQHRSRYTFGQGTKLTVLCD3_sp9arabtor_VLVH EIVMTQSPSTLSASVGDRVIITCKASQNINNYLNWYQQKPGKA 859PKLLIYNTDHLQAGVPSRFSGSGSGAEFTLTISSLQPDDFATYY CLQHRSRYTFGQGTKLTVLCD3_sp11a_VHVL_YY_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_YY_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SANSPTM_YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_YY_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM_S QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_YY_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_YY_s DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_SS_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SANSPTM_YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM_S QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_SS_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_WS_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SANSPTM_YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_WS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM_S QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_WS_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_WS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_WS_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_SW_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SANSPTM_YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SW_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM_S QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_SW_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SW_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_SW_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_TW_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SANSPTM_YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_TW_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM_S QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_TW_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_TW_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_TW_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_TT_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SANSPTM_YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH VL_TT_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM_S QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VHVL_TT_YDIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_TT_S DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VHVL_TT_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855SANSPTM QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_SP11AVH3_VLK_EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSEGTTYFNWYQ 857 3_YQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_ EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSEGTTYFNWYQ 857 3_SQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_ EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSDGTTYFNWYQ 860 3_Y_PTMQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_ EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSDGTTYFNWYQ 860 3_S_PTMQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_ EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSEGTTYFNWYQ 857 3_Y_SWQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_3 EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSEGTTYFNWYQ 857 _S_SWQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_3 EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSDGTTYFNWYQ 860_Y_PTM_SW QKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDLAVYYCLQSSHFPWTFGGGTKVEIK CD3_SP11AVH3_VLK_3EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSDGTTYFNWYQ 860 _S_SWPTMQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_S EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSDGTTYFNWYQ 860 WPTMQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11AVH3_VLK_3 EIVLTQSPGTLSLSPGERATLSCRSSQSLVRSEGTTYFNWYQ 857 _SWQKPGQAPRLLIYRVSNRFSGIPDRFSGSGSGTDFTLTISRLEPE DLAVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_Y DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_S DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 Y_PTMQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 S_PTMQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 Y_SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 S_SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 Y_PTMQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855S_PTM_SW QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_sp11a_VH1_VK2_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_sp11a_VH1_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSEGTTYFNWYQ 855 SW_PTMQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSEGTTYFNWYQ 858 YQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSEGTTYFNWYQ 858 SQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSDGTTYFNWYQ 861 Y_PTMQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSDGTTYFNWYQ 861 S_PTMQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSEGTTYFNWYQ 858 Y_SWQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSEGTTYFNWYQ 858 S_SWQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSDGTTYFNWYQ 861 Y_PTMQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSDGTTYFNWYQ 861S_PTM_SW QKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQSSHFPWTFGGGTKVEIK CD3_SP11A_VH3_VLK1_DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSDGTTYFNWYQ 861 PTM_SWQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH3_VLK1_ DIQMTQSPSSLSASVGDRVTITCRSSQSLVRSEGTTYFNWYQ 858 SWQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 YQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 Y_PTMQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 S_PTMQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 Y_SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 S_SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843Y_PTM_SW QRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCLQSSHFPWTFGGGTKVEIK CD3_SP11A_VH5_VK2_DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 S_PTM_SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 PTM_SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIKCD3_SP11A_VH5_VK2_ DIVMTQTPLSSPVTLGQPASISCRSSQSLVRSDGTTYFNWYQ 843 SWQRPGQPPRLLIYRVSNRFSGVPDRFSGSGAGTDFTLKISRVEA EDVGVYYCLQSSHFPWTFGGGTKVEIK

The group C1 CDR sequences in Table AA are based upon the Kabat CDRsequences, Chothia CDR sequences, IMGT CDR sequences, and combinationsthereof, of the CD3 binding molecules NOV292, NOV589, NOV567, and theCD3 binding molecules which include “sp11a” in the binder name. Thegroup C2 CDR sequences in Table AB are based upon the Kabat CDRsequences, Chothia CDR sequences, IMGT CDR sequences, and combinationsthereof, of the CD3 binding molecules NOV453, NOV229, NOV580, NOV221,and the CD3 binding molecules which include “sp9a” in the binder name.The group C3 CDR sequences in Table AC are based upon the Kabat CDRsequences, Chothia CDR sequences, IMGT CDR sequences, and combinationsthereof, of the CD3 binding molecules NOV123, sp10b, NOV110, and NOV832.

The specific CDR sequences of the CD3 binding molecules described in theExamples of WO 2020/052692 are listed in Table AB-1 to Table AH-2. VHand VL sequences described in WO 2020/052692 are listed in Table AJ-1and Table AJ-2, respectively.

In some embodiments, a CD3 ABM can comprise a heavy chain CDR having anamino acid sequence of any one of the CDR consensus sequences listed inTable AA, Table AB, or Table AC. In particular embodiments, a CD3 ABMcan comprise (or alternatively, consist of) one, two, three, or moreheavy chain CDRs selected from the heavy chain CDRs described in TableAA, Table AB, or Table AC.

In some embodiments, a CD3 ABM can comprise a light chain CDR having anamino acid sequence of any one of the CDR consensus sequences listed inTable AA, Table AB, or Table AC. In particular embodiments, a CD3 ABMcan comprise (or alternatively, consist of) one, two, three, or morelight chain CDRs selected from the light chain CDRs described in TableAA, Table AB, or Table AC.

In some embodiments, a CD3 ABM can comprise a CDR-H1 sequence, a CDR-H2sequence a CDR-H3 sequence, a CDR-L1 sequence, a CDR-L2 sequence, and aCDR-L3 sequence set forth in Table AA.

In some embodiments, the amino acid designated X₁ in Table AA is T. Insome embodiments, the amino acid designated X₁ in Table AA is A. In someembodiments, the amino acid designated X₂ in Table AA is S. In someembodiments, the amino acid designated X₂ in Table AA is R. In someembodiments, the amino acid designated X₃ in Table AA is N. In someembodiments, the amino acid designated X₃ in Table AA is Y. In someembodiments, the amino acid designated X₃ in Table AA is Q. In someembodiments, the amino acid designated X₄ in Table AA is H. In someembodiments, the amino acid designated X₄ in Table AA is S. In someembodiments, the amino acid designated X₅ in Table AA is M. In someembodiments, the amino acid designated X₅ in Table AA is L. In someembodiments, the amino acid designated X₆ in Table AA is K. In someembodiments, the amino acid designated X₆ in Table AA is R. In someembodiments, the amino acid designated X₇ in Table AA is S. In someembodiments, the amino acid designated X₇ in Table AA is K. In someembodiments, the amino acid designated X₅₅ in Table AA is F. In someembodiments, the amino acid designated X₅₅ in Table AA is Y. In someembodiments, the amino acid designated X₅₅ in Table AA is S. In someembodiments, the amino acid designated X₈ in Table AA is W. In someembodiments, the amino acid designated X₈ in Table AA is Y. In someembodiments, the amino acid designated X₈ in Table AA is S. In someembodiments, the amino acid designated X₈ in Table AA is T. In someembodiments, the amino acid designated X₉ in Table AA is W. In someembodiments, the amino acid designated X₉ in Table AA is Y. In someembodiments, the amino acid designated X₉ in Table AA is S. In someembodiments, the amino acid designated X₉ in Table AA is T. In someembodiments, the amino acid designated X₁₀ in Table AA is H. In someembodiments, the amino acid designated Xio in Table AA is Y. In someembodiments, the amino acid designated X₁₁ in Table AA is S. In someembodiments, the amino acid designated X₁₁ in Table AA is G. In someembodiments, the amino acid designated X₁₂ in Table AA is I. In someembodiments, the amino acid designated X₁₂ in Table AA is L. In someembodiments, the amino acid designated X₁₃ in Table AA is V. In someembodiments, the amino acid designated X₁₃ in Table AA is G. In someembodiments, the amino acid designated X₁₄ in Table AA is R. In someembodiments, the amino acid designated X₁₄ in Table AA is N. In someembodiments, the amino acid designated X₁₅ in Table AA is D. In someembodiments, the amino acid designated X₁₅ in Table AA is E. In someembodiments, the amino acid designated X₁₅ in Table AA is L. In someembodiments, the amino acid designated X₁₆ in Table AA is G. In someembodiments, the amino acid designated X₁₆ in Table AA is N. In someembodiments, the amino acid designated X₁₆ in Table AA is E. In someembodiments, the amino acid designated X₁₇ in Table AA is R. In someembodiments, the amino acid designated X₁₇ in Table AA is S. In someembodiments, the amino acid designated X₁₈ in Table AA is V. In someembodiments, the amino acid designated X₁₈ in Table AA is T. In someembodiments, the amino acid designated X₁₉ in Table AA is N. In someembodiments, the amino acid designated X₁₉ in Table AA is T. In someembodiments, the amino acid designated X₂₀ in Table AA is R. In someembodiments, the amino acid designated X₂₀ in Table AA is L. In someembodiments, the amino acid designated X₂₁ in Table AA is F. In someembodiments, the amino acid designated X₂₁ in Table AA is E. In someembodiments, the amino acid designated X₂₂ in Table AA is S. In someembodiments, the amino acid designated X₂₂ in Table AA is Y. In someembodiments, the amino acid designated X₂₃ in Table AA is S. In someembodiments, the amino acid designated X₂₃ in Table AA is Y. In someembodiments, the amino acid designated X₂₄ in Table AA is S. In someembodiments, the amino acid designated X₂₄ in Table AA is A. In someembodiments, the amino acid designated X₂₅ in Table AA is H. In someembodiments, the amino acid designated X₂₅ in Table AA is T. In someembodiments, the amino acid designated X₂₆ in Table AA is F. In someembodiments, the amino acid designated X₂₆ in Table AA is Y. In someembodiments, the amino acid designated X₂₇ in Table AA is W. In someembodiments, the amino acid designated X₂₇ in Table AA is Y.

In some embodiments, a CD3 ABM can comprise the CDR-H1 sequence C1-1. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C1-2. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C1-3. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C_(1-4.)

In some embodiments, a CD3 ABM can comprise the CDR-H2 sequence C1-5. Insome embodiments, a CD3 ABM can comprise the CDR-H2 sequence C1-6. Insome embodiments, a CD3 ABM can comprise the CDR-H2 sequence C1-7.

In some embodiments, a CD3 ABM can comprise the CDR-H3 sequence C1-8. Insome embodiments, a CD3 ABM can comprise the CDR-H3 sequence C1-9. Insome embodiments, a CD3 ABM can comprise the CDR-H3 sequence C1-10. Insome embodiments, a CD3 ABM can comprise the CDR-H3 sequence C1-11.

In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C1-12.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C1-13.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C1-14.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C1-15.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C1-16.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C1-17.

In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C1-18.In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C1-19.

In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C1-20.In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C1-21.In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C1-22.In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C1-23.

In some embodiments, a CD3 ABM can comprise a CDR-H1 sequence, a CDR-H2sequence a CDR-H3 sequence, a CDR-L1 sequence, a CDR-L2 sequence, and aCDR-L3 sequence set forth in Table AB.

In some embodiments, the amino acid designated X₂₈ in Table AB is V. Insome embodiments, the amino acid designated X₂₈ in Table AB is I. Insome embodiments, the amino acid designated X₂₉ in Table AB is F. Insome embodiments, the amino acid designated X₂₉ in Table AB is Y. Insome embodiments, the amino acid designated X₃₀ in Table AB is N. Insome embodiments, the amino acid designated X₃₀ in Table AB is S. Insome embodiments, the amino acid designated X₃₁ in Table AB is A. Insome embodiments, the amino acid designated X₃₁ in Table AB is S. Insome embodiments, the amino acid designated X₃₂ in Table AB is T. Insome embodiments, the amino acid designated X₃₂ in Table AB is K. Insome embodiments, the amino acid designated X₃₃ in Table AB is T. Insome embodiments, the amino acid designated X₃₃ in Table AB is A. Insome embodiments, the amino acid designated X₃₄ in Table AB is S. Insome embodiments, the amino acid designated X₃₄ in Table AB is R. Insome embodiments, the amino acid designated X₃₅ in Table AB is N. Insome embodiments, the amino acid designated X₃₅ in Table AB is G. Insome embodiments, the amino acid designated X₃₆ in Table AB is S. Insome embodiments, n the amino acid designated X₃₆ in Table AB is A. Insome embodiments, the amino acid designated X₃₇ in Table AB is A. Insome embodiments, the amino acid designated X₃₇ in Table AB is T. Insome embodiments, the amino acid designated X₃₇ in Table AB is S. Insome embodiments, the amino acid designated X₃₈ in Table AB is N. Insome embodiments, the amino acid designated X₃₈ in Table AB is D. Insome embodiments, the amino acid designated X₃₉ in Table AB is N. Insome embodiments, the amino acid designated X₃₉ in Table AB is K. Insome embodiments, the amino acid designated X₄₀ in Table AB is D. Insome embodiments, the amino acid designated X₄₀ in Table AB is N. Insome embodiments, the amino acid designated X₄₁ in Table AB is H. Insome embodiments, the amino acid designated X₄₁ in Table AB is N. Insome embodiments, the amino acid designated X₄₂ in Table AB is Q. Insome embodiments, the amino acid designated X₄₂ in Table AB is E. Insome embodiments, the amino acid designated X₄₃ in Table AB is R. Insome embodiments, the amino acid designated X₄₃ in Table AB is S. Insome embodiments, the amino acid designated X₄₃ in Table AB is G.

In some embodiments, a CD3 ABM can comprise the CDR-H1 sequence C2-1. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C2-2.Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C2-3. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C2-4.

In some embodiments, a CD3 ABM can comprise the CDR-H2 sequence C2-5. Insome embodiments, a CD3 ABM can comprise the CDR-H2 sequence C2-6. Insome embodiments, a CD3 ABM can comprise the CDR-H2 sequence C2-7.

In some embodiments, a CD3 ABM can comprise the CDR-H3 sequence C2-8. Insome embodiments, a CD3 ABM can comprise the CDR-H3 sequence C2-9.

In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C2-10.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C2-11.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C2-12.

In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C2-13.In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C2-14.In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C2-15.

In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C2-16.In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C2-17.

In some embodiments, a CD3 ABM can comprise a CDR-H1 sequence, a CDR-H2sequence a CDR-H3 sequence, a CDR-L1 sequence, a CDR-L2 sequence, and aCDR-L3 sequence set forth in Table AC.

In some embodiments, the amino acid designated X₄₄ in Table AC is G. Insome embodiments, the amino acid designated X₄₄ in Table AC is A. Insome embodiments, the amino acid designated X₄₅ in Table AC is H. Insome embodiments, the amino acid designated X₄₅ in Table AC is N. Insome embodiments, the amino acid designated X₄₆ in Table AC is D. Insome embodiments, the amino acid designated X₄₆ in Table AC is G. Insome embodiments, the amino acid designated X₄₇ in Table AC is A. Insome embodiments, the amino acid designated X₄₇ in Table AC is G. Insome embodiments, the amino acid designated X₄₈ in Table AC is N. Insome embodiments, the amino acid designated X₄₈ in Table AC is K. Insome embodiments, the amino acid designated X₄₉ in Table AC is V. Insome embodiments, the amino acid designated X₄₉ in Table AC is A. Insome embodiments, the amino acid designated X₅₀ in Table AC is N. Insome embodiments, the amino acid designated X₅₀ in Table AC is V. Insome embodiments, the amino acid designated X₅₁ in Table AC is A. Insome embodiments, the amino acid designated X₅₁ in Table AC is V. Insome embodiments, the amino acid designated X₅₂ in Table AC is Y. Insome embodiments, the amino acid designated X₅₂ in Table AC is F. Insome embodiments, the amino acid designated X₅₃ in Table AC is I. Insome embodiments, the amino acid designated X₅₃ in Table AC is V. Insome embodiments, the amino acid designated X₅₄ in Table AC is I. Insome embodiments, the amino acid designated X₅₄ in Table AC is H.

In some embodiments, a CD3 ABM can comprise the CDR-H1 sequence C₃-1. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C₃-2. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C₃-3. Insome embodiments, a CD3 ABM can comprise the CDR-H1 sequence C₃-4.

In some embodiments, a CD3 ABM can comprise the CDR-H2 sequence C₃-5. Insome embodiments, a CD3 ABM can comprise the CDR-H2 sequence C₃-6. Insome embodiments, a CD3 ABM can comprise the CDR-H2 sequence C₃-7.

In some embodiments, a CD3 ABM can comprise the CDR-H3 sequence C₃-8. Insome embodiments, a CD3 ABM can comprise the CDR-H3 sequence C₃-9.

In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C₃-10.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C₃-11.In some embodiments, a CD3 ABM can comprise the CDR-L1 sequence C₃-12.

In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C₃-13.In some embodiments, a CD3 ABM can comprise the CDR-L2 sequence C₃-14.

In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C₃-15.In some embodiments, a CD3 ABM can comprise the CDR-L3 sequence C₃-16.

In some embodiments, a CD3 ABM can comprise CDR-H1, CDR-H2, and CDR-H3sequences set forth in Table AD-1 and the corresponding CDR-L1, CDR-L2,and CDR-L3 sequences set forth in Table AD-2.

In some embodiments, a CD3 ABM can comprise CDR-H1, CDR-H2, and CDR-H3sequences set forth in Table AE-1 and the corresponding CDR-L1, CDR-L2,and CDR-L3 sequences set forth in Table AE-2.

In some embodiments, a CD3 ABM can comprise CDR-H1, CDR-H2, and CDR-H3sequences set forth in Table AF-1 and the corresponding CDR-L1, CDR-L2,and CDR-L3 sequences set forth in Table AF-2.

In some embodiments, a CD3 ABM can comprise CDR-H1, CDR-H2, and CDR-H3sequences set forth in Table AG-1 and the corresponding CDR-L1, CDR-L2,and CDR-L3 sequences set forth in Table AG-2.

In some embodiments, a CD3 ABM can comprise CDR-H1, CDR-H2, and CDR-H3sequences set forth in Table AH-1 and the corresponding CDR-L1, CDR-L2,and CDR-L3 sequences set forth in Table AH-2.

In some embodiments, a CD3 ABM can comprise CDR-H1, CDR-H2, and CDR-H3sequences set forth in Table AI-1 and the corresponding CDR-L1, CDR-L2,and CDR-L3 sequences set forth in Table AI-2.

In some embodiments, a CD3 ABM can comprise a heavy chain CDR having anamino acid sequence of any one of the CDRs listed in Table AB-1, TableAC-1, Table AD-1, Table AE-1, Table AF-1, Table AG-1, Table AH-1, orTable AI-1. In particular embodiments, a CD3 ABM can comprise (oralternatively, consist of) one, two, three, or more heavy chain CDRsselected the heavy chain CDRs described in Table AB-1, Table AC-1, TableAD-1, Table AE-1, Table AF-1, Table AG-1, Table AH-1, and Table AI-1.

In some embodiments, a CD3 ABM can comprise a light chain CDR having anamino acid sequence of any one of the CDRs listed in Table AB-2, TableAC-2, Table AD-2, Table AE-2, Table AF-2, Table AG-2, Table AH-2, orTable AI-2. In particular embodiments, a CD3 ABM can comprise (oralternatively, consist of) one, two, three, or more light chain CDRsselected the light chain CDRs described in Table AB-2, Table AC-2, TableAD-2, Table AE-2, Table AF-2, Table AG-2, Table AH-2, and Table AI-2.

Other CD3 ABMs include amino acids that have been mutated, yet have atleast 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in the CDRregions with the CDR sequences described in Table A. In someembodiments, such CD3 ABMs include mutant amino acid sequences where nomore than 1, 2, 3, 4 or 5 amino acids have been mutated in the CDRregions when compared with the CDR sequences described in Table A.

In some embodiments, a CD3 ABM can comprise a VH and/or VL domain havingan amino acid sequence of any VH and/or VL domain described in Table A.Other CD3 ABMs include VH and/or VL domains comprising amino acidsequences having at least 80, 85, 90, 95, 96, 97, 98, or 99 percentidentity to the VH and/or VL sequences described in Table A. In someembodiments, CD3 ABMs include VH and/or VL domains where no more than 1,2, 3, 4 or 5 amino acids have been mutated when compared with the VHand/or VL domains depicted in the sequences described in Table A, whileretaining substantially the same therapeutic activity.

VH and VL sequences (amino acid sequences and the nucleotide sequencesencoding the amino acid sequences) can be “mixed and matched” to createother CD3 ABMs. Such “mixed and matched” CD3 ABMs can be tested usingbinding assays known in the art (e.g., FACS assays). When chains aremixed and matched, a VH sequence from a particular VH/VL pairing shouldbe replaced with a structurally similar VH sequence. A VL sequence froma particular VH/VL pairing should be replaced with a structurallysimilar VL sequence.

Accordingly, in one embodiment, a CD3 ABM comprises: a heavy chainvariable region (VH) comprising an amino acid sequence selected from anyone of the VH sequences described in Table A-J1; and a light chainvariable region (VL) comprising an amino acid sequence described inTable A-J2.

In some embodiments, the antigen-binding domain that specifically bindsto human CD3 is non-immunoglobulin based and is instead derived from anon-antibody scaffold protein, for example one of the non-antibodyscaffold proteins described in Section 7.2.2. In an embodiment, theantigen-binding domain that specifically binds to human CD3 comprisesAffilin-144160, which is described in WO 2017/013136. Affilin-144160 hasthe following amino acid sequence:

(SEQ ID NO: 498) MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQWLWFAGKQLEDGRTLSDYNIQKESTLKLWLVDKAAMQIFVYTRTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIWAGKQLEDGRTLSDYNIALESGLHLVL RLRAA 

7.6.2. TCR-α/β ABMs

The MBMs (e.g., TBMs) can contain an ABM that specifically binds to theTCR-α chain, the TCR-β chain, or the TCR-αβ dimer. Exemplaryanti-TCR-α/β antibodies are known (see, e.g., US 2012/0034221; Borst etal., 1990, Hum Immunol. 29(3):175-88 (describing antibody BMA031)). TheVH, VL, and Kabat CDR sequences of antibody BMA031 are provided in Table13.

TABLE 13 BMA031 sequences SEQ ID Domain Sequence NO: BMA031KASGYKFTSYVMH 499 CDR-H1 BMA031 YINPYNDVTKYNEKFK 500 CDR-H2 BMA031GSYYDYDGFVY 501 CDR-H3 BMA031 SATSSVSYMH 502 CDR-L1 BMA031 DTSKLAS 406CDR-L2 BMA031 QQWSSNPLT 435 CDR-L3 BMA031EVQLQQSGPELVKPGASVKMSCKASGYKFTSYVMHWVKQKPGQGLE 503 VHWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSA BMA031QIVLTQSPAIMSASPGEKVTMTCSATSSVSYMHWYQQKSGTSPKRWI 504 VLYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNP LTFGAGTKLELK

In an embodiment, an ABM2 can comprise the CDR sequences of antibodyBMA031. In other embodiments, an ABM2 can comprise the VH and VLsequences of antibody BMA031.

7.6.3. TCR- γ/∂ ABMs

The MBMs (e.g., TBMs) can contain an ABM that specifically binds to theTCR- y chain, the TCR-δ chain, or the TCR- γδ dimer. Exemplaryanti-TCR-γ/δ antibodies are known (see, e.g., U.S. Pat. No. 5,980,892(describing δTCS1, produced by the hybridoma deposited with the ATCC asaccession number HB 9578)).

7.7. CD2 ABMs

7.7.1. Immunoglobulin-Based CD2 ABMs

A MBM (e.g., a TBM) can comprise an ABM which is an anti-CD2 antibody oran antigen-binding domain thereof. Exemplary anti-CD2 antibodies areknown (see, e.g., U.S. Pat. No. 6,849,258, CN102827281A, US 2003/0139579Al, and U.S. Pat. No. 5,795,572). Table 14 provides exemplary CDR, VH,and VL sequences that can be included in anti-CD2 antibodies orantigen-binding fragments thereof, for use in MBMs of the disclosure.

TABLE 14 Immunoglobulin Based CD2 Binders SEQ ID Name Domain SequenceNO: CD2-1 CDR-H1 EYYMY (Rat Lo-CD2a = BTI-322 from FIG. 33 of USP 5056,849,258) CD2-1 CDR-H2RIDPEDGSIDYVEKFKK (Rat Lo-CD2a = BTI-322 from FIG. 50633 of USP 6,849,258) CD2-1 CDR-H3GKFNYRFAY (Rat Lo-CD2a = BTI-322 from Fig. 33 of USP 507 6,849,258)CD2-1 CDR-L1 RSSQSLLHSSGNTYLN (Rat Lo-CD2a = BTI-322 from FIG. 50831 of USP 6,849,258) CD2-1 CDR-L2LVSKLES (Rat Lo-CD2a = BTI-322 from FIG. 31 of USP 509 6,849,258) CD2-1CDR-L3 QFTHYPYT (Rat Lo-CD2a = BTI-322 from FIG. 31 of USP 5106,849,258) CD2-1 VH EVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQR 511PKQGLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSS (SEQ ID NO: 100 of USP 6,849,258)CD2-1 VL DVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLL 512QRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELK (Rat Lo-CD2a Vkfrom SEQ ID NO: 92, without signal sequence as shownin FIG. 31 of USP 6,849,258) hu1CD2-1 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQ 513APGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSS (SEQ ID NO: 101 of USP 6,849,258)VL DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWL 514LQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK (SEQ ID NO: 96 of USP 6,849,258) hu2CD2-1VH EVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQR 511PKQGLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSS (Vhof MEDI-507; SEQ ID NO: 105 of USP 6,849,258) VLDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWL 514LQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK (SEQ ID NO: 96of USP 6,849,258)(same as hu1CD2-1)

In some embodiments, a CD2 ABM comprises the CDR sequences of CD2-1 (SEQID NOS: 505-510). In some embodiments, a CD2 ABM comprises the heavy andlight chain variable sequences of CD2-1 (SEQ ID NOS: 511-512). In someembodiments, a CD2 ABM comprises the heavy and light chain variablesequences of hu1CD2-1 (SEQ ID NOS: 513-514). In some embodiments, a CD2ABM comprises the heavy and light chain variable sequences of hu2CD2-1(SEQ ID NOS: 511 and 514, respectively).

In other embodiments, a CD2 ABM can comprise the CDR sequences ofantibody 9D1 produced by the hybridoma deposited with the ChineseCulture Collection Committee General Microbiology Center on May 16, 2012with accession no. CGMCC 6132, and which is described in CN102827281A.In other embodiments, a CD2 ABM can comprise the CDR sequences ofantibody LO-CD2b produced by the hybridoma deposited with the AmericanType Culture Collection on Jun. 22, 1999 with accession no. PTA-802, andwhich is described in US 2003/0139579 Al. In yet other embodiments, aCD2 ABM can comprise the CDR sequences of the CD2 SFv-Ig produced byexpression of the construct cloned in the recombinant E. coli depositedwith the ATCC on Apr. 9, 1993 with accession no. 69277, and which isdescribed in U.S. Pat. No. 5,795,572.

In other embodiments, a CD2 ABM can comprise the VH and VL sequences ofantibody 9D1. In other embodiments, a CD2 ABM can comprise the VH and VLsequences of antibody LO-CD2b. In yet other embodiments, a CD2 ABM cancomprise the VH and VL sequences of the CD2 SFv-Ig produced byexpression of the construct cloned in the recombinant E. coli havingATCC accession no. 69277.

7.7.2. CD58-Based CD2 ABMs

In certain aspects the present disclosure provides a MBM comprising aCD2 ABM which is a ligand. The CD2 ABM specifically binds to human CD2,whose natural ligand is CD58, also known as LFA-3. CD58/LFA-3 proteinsare glycoproteins that are expressed on the surfaces of a variety ofcell types (Dustin et al., 1991, Annu. Rev. Immunol. 9:27) and playroles in mediating T-cell interactions with APCs in bothantigen-dependent and antigen-independent manners (Wallner et al., 1987,J. Exp. Med. 166:923). Accordingly, in certain aspects, the CD2 ABM is aCD58 moiety. As used herein, a CD58 moiety comprises an amino acidsequence comprising at least 70% sequence identity to a CD2-bindingportion of CD58, e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%,78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a CD2-bindingportion of CD58. The sequence of human CD58 has the Uniprot identifierP19256 (www.uniprot.org/uniprot/P19256). It has been established thatCD58 fragments containing amino acid residues 30-123 of full length CD58(i.e., the sequence designated as CD58-6 in Table 15 below) aresufficient for binding to CD2. Wang et al., 1999, Cell 97:791-803.Accordingly, in certain aspects, a CD58 moiety comprises an amino acidsequence comprising at least 70% sequence identity to amino acids 30-123of CD58, e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequencedesignated CD58-6.

The interactions between CD58 and CD2 have been mapped through x-raycrystallography and molecular modeling. The substitution of residuesE25, K29, K30, K32, D33, K34, E37, D84 and K87 (with numbering referringto the in the mature polypeptide) reduces binding to CD2. Ikemizu etal., 1999, Proc. Natl. Acad. Sci. USA 96:4289-94. Accordingly, in someembodiments the CD58 moiety retains the wild type residues at E25, K29,K30, K32, D33, K34, E37, D84 and K87.

In contrast, the following substitutions (with numbering referring tothe full length polypeptide) did not impact binding to CD2: F29S; V37K;V49Q; V86K; T113S; and L121G. Accordingly, a CD58 moiety can includeone, two, three, four, five or all six of the foregoing substitutions.

In some embodiments, the CD58 moiety is engineered to include a pair ofcysteine substitutions that upon recombinant expression create adisulfide bridge. Exemplary amino acid pairs that can be substitutedwith cysteines in order to form a disulfide bridge upon expression (withnumbering referring to the full length polypeptide) are (a) a V45Csubstitution and a M105C substitution; (b) a V54C substitution and aG88C substitution; (c) a V45C substitution and a M114C substitution; and(d) a W56C substitution and a L90C substitution.

Exemplary CD58 moieties are provided in Table 15 below:

TABLE 15 CD58 sequences Name Description Sequence SEQ ID NO: CD58-1Full length CD58, MVAGSDAGRALGVLSVVCLLHCFGFISCFSQQIYGVVY 515including signal GNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFS sequence and fullSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTM intracellular domainKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEHYNSHRG (P19256)LIMYSWDCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIPSSGHSRHRYALIPIPLAVITTCIVLY MNGILKCDRKPDRTNSN CD58-2Full length CD58, MVAGSDAGRALGVLSVVCLLHCFGFISCFSQQIYGVVY 516including signal GNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFS sequence and butSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTM no intracellularKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEHYNSHRG domain (P19256-2)LIMYSWDCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIPSSGHSRHRYALIPIPLAVITTCIVLY MNVL CD58-3 Full length CD58,MVAGSDAGRALGVLSVVCLLHCFGFISCFSQQIYGVVY 517 including signalGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFS sequence andSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTM variant intracellularKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEHYNSHRG domain (P19256-3)LIMYSWDCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIPSSGHSRHRYALIPIPLAVITTCIVLY MNGILKCDRKPDRTK CD58-4Extracellular domain FSQQIYGVVYGNVTFHVPSNVPLKEVLWKKQKDKVAE 518 of CD58,LENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYE corresponding toMESPNITDTMKFFLYVLESLPSPTLTCALTNGSIEVQCM amino acids 29-215IPEHYNSHRGLIMYSWDCPMEQCKRNSTSIYFKMENDL of CD58 (WT)PQKIQCTLSNPLFNTTSSIILTTCIPSSGHSRHR CD58-5 Extracellular domainBSQQIYGVJYGNVTFHVPSNOPLKEVLWKKQKDK 519 of CD58,VAELENSEFRAFSSFKNRVYLDTUSGSLTIYNLTS corresponding toSDEDEYEMESPNITDXMKFFLYVZESLPSPTLTCA amino acids 29-215LTNGSIEVQCMIPEHYNSHRGLIMYSWDCPMEQC of CD58 (withKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILT permitted TCIPSSGHSRHRsubstitutions) B = F or S J = V or K O = V or Q U = V or K X = T or SZ = L or G CD58-6 Amino acids 30-123SQQIYGVVYGNVTFHVPSNVPLKEVLWKKQKDKVAEL 520 (WT)ENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYE Ig-V like domainMESPNITDTMKFFLYVLES CD58-7 Amino acids 30-123SQQIYGVJYGNVTFHVPSNOPLKEVLWKKQKDKVAEL 521 (with permittedENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYE substitutions)MESPNITDTMKFFLYVLES Ig-V like domain J = V or K O = V or Q CD58-8Amino acids 30-123 SQQIYGVVYGNVTFHCPSNVPLKEVLWKKQKDKVAEL 522(V45C_M105C) ENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYE Ig-V like domainCESPNITDTMKFFLYVLES CD58-9 Amino acids 30-123SQQIYGVVYGNVTFHVPSNVPLKECLWKKQKDKVAEL 523 (V54C_G88C)ENSEFRAFSSFKNRVYLDTVSCSLTIYNLTSSDEDEYE Ig-V like domainMESPNITDTMKFFLYVLES CD58-10 Amino acids 30-123SQQIYGVVYGNVTFHCPSNVPLKEVLWKKQKDKVAEL 524 (V45C_M114C)ENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYE Ig-V like domainMESPNITDTCKFFLYVLES CD58-11 Amino acids 30-123SQQIYGVVYGNVTFHVPSNVPLKEVLCKKQKDKVAELE 525 (W56C_L90C)NSEFRAFSSFKNRVYLDTVSGSCTIYNLTSSDEDEYEM Ig-V like domainESPNITDTMKFFLYVLES

7.7.3. CD48-Based CD2 ABMs

In certain aspects the present disclosure provides a MBM comprising aCD2 ABM which is CD48 moiety. As used herein, a CD48 moiety comprises anamino acid sequence comprising at least 70% sequence identity to aCD2-binding portion of CD48, e.g., at least 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to aCD2-binding portion of CD48. The sequence of human CD48 has the Uniprotidentifier P09326 (www.uniprot.org/uniprot/P09326), which includes asignal peptide (amino acids 1-26) and a GPI anchor (amino acids221-243). In certain aspects, a CD48 moiety comprises an amino acidsequence comprising at least 70% sequence identity (e.g., at least 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% identity) to the amino acid sequence consisting of amino acids27-220 of Uniprot identifier P09326. Human CD48 has an Ig-like 02-type Idomain (amino acids 29-127 of Uniprot identifier P09326) and a Ig-likeC2 type 2 domain (amino acids 132-212 of Uniprot identifier P09326).Accordingly, in some embodiments, a CD48 moiety comprises an amino acidsequence comprising at least 70% sequence identity (e.g., at least 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% identity) to the amino acid sequence consisting of amino acids29-212 of Uniprot identifier P09326, to the 02-type I domain (aminoacids 29-127 of Uniprot identifier P09326) and/or to the Ig-like C2 type2 domain (amino acids 132-212 of Uniprot identifier P09326). A CD48moiety can in some embodiments comprise one or more natural variantsrelative to the sequence of Uniprot identifier P09326. For example, aCD48 moiety can include a E102Q substitution. As another example, a CD48moiety can comprise an amino acid sequence corresponding to a CD-48isoform or a CD2 binding portion thereof, e.g., the isoform havingUniprot identifier P09326-2 or a CD2 binding portion thereof.

7.8. Tumor-Associated Antigen ABMs

The MBMs (e.g., TBMs) can comprise an ABM that binds specifically to atumor-associated antigen (TAA). In some embodiments, the TAA is a humanTAA. The antigen may or may not be present on normal cells. In certainembodiments, the TAA is preferentially expressed or upregulated on tumorcells as compared to normal cells. In other embodiments, the TAA is alineage marker.

In certain embodiments, the TAA is expressed or upregulated on cancerousB cells as compared to normal B cells. In other embodiments, the TAA isa B cell lineage marker.

It is anticipated that any type of B cell malignancy can be targeted bythe MBMs of the disclosure. Exemplary types of B cell malignancies thatcan be targeted include Hodgkin's lymphomas, non-Hodgkin's lymphomas(NHLs), and multiple myeloma. Examples of NHLs include diffuse largeB-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocyticleukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma(MCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacyticlymphoma (Waldenstrom macroglobulinemia), hairy cell leukemia, primarycentral nervous system (CNS) lymphoma, primary mediastinal large B-celllymphoma, mediastinal grey-zone lymphoma (MGZL), splenic marginal zoneB-cell lymphoma, extranodal marginal zone B-cell lymphoma of MALT, nodalmarginal zone B-cell lymphoma, and primary effusion lymphoma.

Examples of TAAs that can be targeted by the MBMs (e.g., TBMs) includeCD19, CD20, CD22, CD123, CD33, CLL1, CD138 (also known as Syndecan-1,SDC1), CS1, CD38, CD133, FLT3, CD52, TNFRSF13C (TNF Receptor SuperfamilyMember 13C, also referred to in the art as BAFFR: B-Cell-ActivatingFactor Receptor), TNFRSF13B (TNF Receptor Superfamily Member 13B, alsoreferred to in the art as TACI: Transmembrane Activator And CAMLInteractor), CXCR4 (C-X-C Motif Chemokine Receptor 4), PD-L1 (programmeddeath-ligand 1), LY9 (lymphocyte antigen 9, also referred to in the artas CD229), CD200, FCGR2B (Fc fragment of IgG receptor Ilb, also referredto in the art as CD32b), CD21, CD23, CD24, CD4OL, CD72, CD79a, andCD79b. In some embodiments, the TAA is CD19. In some embodiments, theTAA is CD20. In some embodiments, the TAA is CD22. In some embodiments,the TAA is CD123. In some embodiments, the TAA is CD33. In someembodiments, the TAA is CLL1. In some embodiments, the TAA is CD138. Insome embodiments, the TAA is CS1. In some embodiments, the TAA is CD38.In some embodiments, the TAA is CD133. In some embodiments, the TAA isFLT3. In some embodiments, the TAA is CD52. In some embodiments, the TAAis TNFRSF13C. In some embodiments, the TAA is TNFRSF13B. In someembodiments, the TAA is CXCR4. In some embodiments, the TAA is PD-L1. Insome embodiments, the TAA is LY9. In some embodiments, the TAA is CD200.In some embodiments, the TAA is CD21. In some embodiments, the TAA isCD23. In some embodiments, the TAA is CD24. In some embodiments, the TAAis CD4OL. In some embodiments, the TAA is CD72. In some embodiments, theTAA is CD79a. In some embodiments, the TAA is CD79b.

A TAA-binding ABM can comprise, for example, an anti-TAA antibody or anantigen-binding fragment thereof. The anti-TAA antibody orantigen-binding fragment can comprise, for example, the CDR sequences ofan antibody set forth in Table 16. In some embodiments, the anti-TAAantibody or antigen-binding domain thereof has the heavy and light chainvariable region sequences of an antibody set forth in Table 16.

TABLE 16 Exemplary Anti-Tumor-Associated Antigen Antibodies TargetExamples of Antibody Name and/or Reference(s) and/or Source CD123 AnyCD123 antibody described in U.S. Pat. No. 8,852,551, EP2426148, WO2014/138819, WO 2016/028896, or WO 2014/130635 CD19 Any CD19 antibodydescribed in WO 2014/031687, WO 2012/079000, WO 2014/153270, or U.S.Pat. No. 7,741,465; the CD19 binder of Yescarta or Blinatumomab CD20Rituximab, Ofatumumab, Ocrelizumab, Veltuzumab, or GA101 CD22 Any CD22antibody described in Haso et al., 2013, Blood, 121(7): 1165-1174, Wayneet al., 2010, Clin Cancer Res 16(6): 1894-1903, Kato et al., 2013, LeukRes 37(1): 83-88, or Creative BioMart (creativebiomart.net):MOM-18047-S(P). CD33 Any CD33 antibody described in Bross et al., 2001,Clin Cancer Res 7(6): 1490- 1496 (Gemtuzumab Ozogamicin, hP67.6), Caronet al., 1992, Cancer Res 52(24): 6761-6767 (Lintuzumab, HuM195), Lapusanet al., 2012, Invest New Drugs 30(3): 1121-1131 (AVE9633), Aigner etal., 2013, Leukemia 27(5): 1107- 1115 (AMG330, CD33 BiTE), Dutour etal., 2012, Adv Hematol 2012: 683065, or Pizzitola et al., 2014, Leukemiadoi: 10.1038/Lue.2014.62. CD38 Daratumumab (see, e.g., Groen et al.,2010, Blood 116(21): 1261-1262; MOR202 (see, e.g., U.S. Pat. No.8,263,746); or any CD38 antibody described in U.S. Pat. No. 8,362,211.CLL-1 PE-CLL1-hu Cat# 353604 (BioLegend); PE-CLL1 (CLEC12A) Cat# 562566(BD); Any CLL-1 antibody described in WO 2014/051433 A1, US 2016/0368994A1, US 2013/0295118 A1, U.S. Pat. No. 8,536,310 B2, Lu et al., 2014,Angewandte Chemie International Edition 53(37): 9841-9845, or Leong etal., 2017, Blood 129(5): 609-618 CS1 Elotuzumab (BMS), see e.g., Tai etal., 2008, Blood 112(4): 1329-37; Tai et al., 2007, Blood. 110(5):1656-63. FLT3 Any FLT3 antibody described in WO 2011/076922, U.S. Pat.No. 5,777,084, EP0754230, or US 2009/0297529. CD133 Any CD133 antibodydescribed in U.S. Pat. No. 9,624,303, WO 2016/154623, or WO 2011/089211;5E3 (ThermoFisher); MAB11331 (R&D Systems); MAB4310 (Millipore Sigma)CD138 Any CD138 antibody described in WO/2009/080829, WO/2017/014679, orU.S. Pat. No. 9,289,509; nBT062 (Biotest AG); MI15, B-A38, SP152, DL-101(ThermoFisher) CD52 alemtuzumab (Genzyme); ANT1034 (see, Holgate et al.,2015, PLOS ONE 10(9): e0138123; any CD52 antibody described inWO/2010/132659; any CD52 antibody described in U.S. Pat No. 9,708,407;any CD52 antibody described in WO/2010/132659 TNFRSF13C Any TNFRSF13Cantibody described in WO 2010/007082, U.S. Pat. No. 9,382,326 TNFRSF13BAny TNFRSF13B antibody described in WO 2004/011611; LS-C89973 (LifespanBiosciences, Inc.) M02952-1 (Boster Biological Technology); MAB1041,MAB1741, and MAB174 (R&D Systems) CXCR4 Any CXCR4 antibody described inU.S. Pat. Nos. 7,138,496, 8,329,178, 8,450,464, 9,249,223, or 9,260,527PD-L1 Any PD-L1 antibody described in US 2015/0203580, US 2017/0058033,US 2017/0204184, U.S. Pat No. 8,741,295, U.S. Pat. No. 9,789,183, orU.S. Pat. No. 9,637,546 LY9 HLy9.25 (e.g., Lifespan Biosciences, Inc.cat. no. LS-C112605); MAB1898 (R&D Systems) CD200 Any CD200 antibodydescribed in U.S. Pat. No. 7,887,798; ab23552 (Abcam); Ox104(ThermoFisher) FCGR2B Any FCGR2B antibody described in U.S. Pat No.8,802,089 or WO 2017/103895; ab45143 (Abcam); AT130-2 (ThermoFisher);2E10 (Millipore Sigma) CD21 ab75985 (Abcam); ab9492 (Abcam); 2G9(ThermoFisher); HB5 (ThermoFisher); MAB4909 (R&D Systems) CD23 Any CD23antibody described in U.S. Pat. No. 7,008,623 or U.S. Pat. No.6,011,138; lumiliximab (Biogen); ab16702 (Abcam); SP23 (ThermoFisher)CD24 Any CD24 antibody described in U.S. Pat. No. 8,614,301; SN3(ThermoFisher); SN3b (ThermoFisher); 2Q1282 (Santa Cruz Biotechnology);3H1143 (Santa Cruz Biotechnology); ALB9 (Santa Cruz Biotechnology);MAB5248 (R&D Systems) CD40L Any CD40L antibody described in U.S. Pat.No. 9,228,018 or US 2003/0099642; 24-31 (Biolegend); ab52750 (Abcam);ab47204 (Abcam); CDP7657 (UCB Pharma); 5e8 (Biogen) CD72 3F3(Biolegend); Bu40 (ThermoFisher); H-7 (Santa Cruz Biotechnology); H-96(Santa Cruz Biotechnology); G-5 (Santa Cruz Biotechnology); ab92509(Abcam) CD79a ab62650 (Abcam); ab79414 (Abcam); MAB69201 (R&D Systems);HM57 (Bio- Rad) CD79b Any CD79b antibody described in WO 2014/011521;ab130422 (Abcam); ab134147 (Abcam); polatuzumab (Genentech)

In certain embodiments, the TAA is selected from CD19 and CD20. In someembodiments, the TAA is CD19. CD19 is a human B-cell marker and is foundon mature B cells but not on plasma cells. CD19 is expressed duringearly pre-B cell development and remains until plasma celldifferentiation. CD19 is expressed on both normal B cells and cancerousB cells whose abnormal growth can lead to B-cell lymphomas. For example,CD19 is expressed on B-cell lineage cancers, including, but not limitedto non-Hodgkin's lymphoma (B-NHL), chronic lymphocytic leukemia, andacute lymphoblastic leukemia.

In certain aspects, a MBM (e.g., a TBM) comprises an ABM3 thatspecifically binds to CD19. Exemplary CDR and variable domain sequencesthat can be incorporated into an ABM that specifically binds to CD19 areset forth in Table 17 below.

TABLE 17 CD19 Binders SEQ ID Name Domain Sequence NO: CD19-H1 CDR-H1DYGVS 526 CD19-H2A CDR-H2 VIWGSETTYYNSALKS 527 CD19-H2B CDR-H2VIWGSETTYYSSSLKS 528 CD19-H2C CDR-H2 VIWGSETTYYQSSLKS 529 CD19-H2DCDR-H2 VIWGSETTYYNSSLKS 530 CD19-H3 CDR-H3 HYYYGGSYAMDY 531 CD19-L1CDR-L1 RASQDISKYLN 532 CD19-L2 CDR-L2 HTSRLHS 533 CD19-L3 CDR-L3QQGNTLPYT 534 CD19-VHA VH EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWI 535RQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWG QGTSVTVSS CD19-VHB VHQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 536RQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWG QGTLVTVSS CD19-VHC VHQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 537RQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWG QGTLVTVSS CD19-VHD VHQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 538RQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWG QGTLVTVSS CD19-VLA VLDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQ 539KPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTIS NLEQEDIATYFCQQGNTLPYTFGGGTKLEITCD19-VLB VL EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 540KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISS LQPEDFAVYFCQQGNTLPYTFGQGTKLEIKCD19-scFv1 scFv EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 541KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGG SYAMDYWGQGTLVTVSS CD19-scFv2 scFvEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 542KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGG SYAMDYWGQGTLVTVSS CD19-scFv3 scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 543RQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFC QQGNTLPYTFGQGTKLEIK CD19-scFv4scFv QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 544RQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFC QQGNTLPYTFGQGTKLEIK CD19-scFv5scFv EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 545KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKH YYYGGSYAMDYWGQGTLVTVSS CD19-scFv6scFv EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 546KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKH YYYGGSYAMDYWGQGTLVTVSS CD19-scFv7scFv QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 547RQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWG QGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPED FAVYFCQQGNTLPYTFGQGTKLEIKCD19-scFv8 scFv QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 548RQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWG QGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPED FAVYFCQQGNTLPYTFGQGTKLEIKCD19-scFv9 scFv EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 549KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKH YYYGGSYAMDYWGQGTLVTVSS CD19- scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 550 scFv10RQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWG QGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPED FAVYFCQQGNTLPYTFGQGTKLEIK CD19-scFv EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQ 551 scFv11KPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGG SYAMDYWGQGTLVTVSS CD19- scFvQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWI 552 scFv12RQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFC QQGNTLPYTFGQGTKLEIK

In certain aspects, ABM3 comprises heavy chain CDRs having the aminoacid sequences of CD19-H1, CD19-H₂A, and CD19-H3 as set forth in Table17 and light chain CDRs having the amino acid sequences of CD19-L1,CD19-L2, and CD19-L3 as set forth in Table 17. In an embodiment, ABM3comprises a heavy chain variable region having the amino acid sequencesof VHA as set forth in Table 17 and a light chain variable region havingthe amino acid sequences of VLA as set forth in Table 17.

In other aspects, ABM3 comprises heavy chain CDRs having the amino acidsequences of CD19-H1, CD19-H₂B, and CD19-H3 as set forth in Table 17 andlight chain CDRs having the amino acid sequences of CD19-L1, CD19-L2,and CD19-L3 as set forth in Table 17. In an embodiment, ABM3 comprises aheavy chain variable region having the amino acid sequences of VHB asset forth in Table 17 and a light chain variable region having the aminoacid sequences of VLB as set forth in Table 17.

In further aspects, ABM3 comprises heavy chain CDRs having the aminoacid sequences of CD19-H1, CD19-H₂C, and CD19-H3 as set forth in Table17 and light chain CDRs having the amino acid sequences of CD19-L1,CD19-L2, and CD19-L3 as set forth in Table 17. In an embodiment, ABM3comprises a heavy chain variable region having the amino acid sequencesof VHC as set forth in Table 17 and a light chain variable region havingthe amino acid sequences of VLB as set forth in Table 17.

In further aspects, ABM3 comprises heavy chain CDRs having the aminoacid sequences of CD19-H1, CD19-H₂D, and CD19-H3 as set forth in Table17 and light chain CDRs having the amino acid sequences of CD19-L1,CD19-L2, and CD19-L3 as set forth in Table 17. In an embodiment, ABM3comprises a heavy chain variable region having the amino acid sequencesof VHD as set forth in Table 17 and a light chain variable region havingthe amino acid sequences of VLB as set forth in Table 17.

In yet further aspects, ABM3 is in the form of an scFV. Exemplaryanti-CD19 scFvs comprise the amino acid sequence of any one ofCD19-scFv1 through CD19-scFv12 as set forth in Table 17.

7.9. Nucleic Acids and Host Cells

In another aspect, the disclosure provides nucleic acids (i.e.,polynucleotides) encoding the MBMs (e.g., TBMs) of the disclosure. Insome embodiments, the MBMs are encoded by a single nucleic acid. Inother embodiments, the MBMs are encoded by a plurality (e.g., two,three, four or more) nucleic acids.

A single nucleic acid can encode a MBM that comprises a singlepolypeptide chain, a MBM that comprises two or more polypeptide chains,or a portion of a MBM that comprises more than two polypeptide chains(for example, a single nucleic acid can encode two polypeptide chains ofa TBM comprising three, four or more polypeptide chains, or threepolypeptide chains of a TBM comprising four or more polypeptide chains).For separate control of expression, the open reading frames encoding twoor more polypeptide chains can be under the control of separatetranscriptional regulatory elements (e.g., promoters and/or enhancers).The open reading frames encoding two or more polypeptides can also becontrolled by the same transcriptional regulatory elements, andseparated by internal ribosome entry site (IR^(E) S) sequences allowingfor translation into separate polypeptides.

In some embodiments, a MBM comprising two or more polypeptide chains isencoded by two or more nucleic acids. The number of nucleic acidsencoding a MBM can be equal to or less than the number of polypeptidechains in the MBM (for example, when more than one polypeptide chainsare encoded by a single nucleic acid).

The nucleic acids can be DNA or RNA (e.g., mRNA).

In another aspect, the disclosure provides host cells and vectorscontaining the nucleic acids of the disclosure. The nucleic acids can bepresent in a single vector or separate vectors present in the same hostcell or separate host cell, as described in more detail herein below.

7.9.1. Vectors

The disclosure provides vectors comprising nucleotide sequences encodinga MBM (e.g., a TBM) or a MBM component described herein. In oneembodiment, the vectors comprise nucleotides encoding animmunoglobulin-based ABM described herein. In one embodiment, thevectors comprise nucleotides encoding an Fc domain described herein. Inone embodiment, the vectors comprise nucleotides encoding a recombinantnon-immunoglobulin based ABM described herein. A vector can encode oneor more ABMs, one or more Fc domains, one or more non-immunoglobulinbased ABM, or any combination thereof (e.g., when multiple components orsub-components are encoded as a single polypeptide chain). In oneembodiment, the vectors comprise the nucleotide sequences describedherein. The vectors include, but are not limited to, a virus, plasmid,cosmid, lambda phage or a yeast artificial chromosome (YAC).

Numerous vector systems can be employed. For example, one class ofvectors utilizes DNA elements which are derived from animal viruses suchas, for example, bovine papilloma virus, polyoma virus, adenovirus,vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV orMOMLV) or SV40 virus. Another class of vectors utilizes RNA elementsderived from RNA viruses such as Semliki Forest virus, Eastern EquineEncephalitis virus and Flaviviruses.

Additionally, cells which have stably integrated the DNA into theirchromosomes can be selected by introducing one or more markers whichallow for the selection of transfected host cells. The marker canprovide, for example, prototropy to an auxotrophic host, biocideresistance (e.g., antibiotics), or resistance to heavy metals such ascopper, or the like. The selectable marker gene can be either directlylinked to the DNA sequences to be expressed, or introduced into the samecell by cotransformation. Additional elements may also be needed foroptimal synthesis of mRNA. These elements can include splice signals, aswell as transcriptional promoters, enhancers, and termination signals.

Once the expression vector or DNA sequence containing the constructs hasbeen prepared for expression, the expression vectors can be transfectedor introduced into an appropriate host cell. Various techniques can beemployed to achieve this, such as, for example, protoplast fusion,calcium phosphate precipitation, electroporation, retroviraltransduction, viral transfection, gene gun, lipid based transfection orother conventional techniques. Methods and conditions for culturing theresulting transfected cells and for recovering the expressedpolypeptides are known to those skilled in the art, and can be varied oroptimized depending upon the specific expression vector and mammalianhost cell employed, based upon the present description.

7.9.2. Cells

The disclosure also provides host cells comprising a nucleic acid of thedisclosure.

In one embodiment, the host cells are genetically engineered to compriseone or more nucleic acids described herein.

In one embodiment, the host cells are genetically engineered by using anexpression cassette. The phrase “expression cassette,” refers tonucleotide sequences, which are capable of affecting expression of agene in hosts compatible with such sequences. Such cassettes can includea promoter, an open reading frame with or without introns, and atermination signal. Additional factors necessary or helpful in effectingexpression can also be used, such as, for example, an induciblepromoter.

The disclosure also provides host cells comprising the vectors describedherein.

The cell can be, but is not limited to, a eukaryotic cell, a bacterialcell, an insect cell, or a human cell. Suitable eukaryotic cellsinclude, but are not limited to, Vero cells, HeLa cells, COS cells, CHOcells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cellsinclude, but are not limited to, Sf9 cells.

7.10. Antibody-Drug Conjugates

The MBMs (e.g., TBMs) can be conjugated, e.g., via a linker, to a drugmoiety. Such conjugates are referred to herein as antibody-drugconjugates (or “ADCs”) for convenience, notwithstanding the fact thatone or more (or all) of the ABMs might be based on non-immunoglobulinscaffolds.

In certain aspects, the drug moiety exerts a cytotoxic or cytostaticactivity. In one embodiment, the drug moiety is chosen from amaytansinoid, a kinesin-like protein KIF11 inhibitor, a V-ATPase(vacuolar-type H+-ATPase) inhibitor, a pro-apoptotic agent, a Bcl2(B-cell lymphoma 2) inhibitor, an MCL1 (myeloid cell leukemia 1)inhibitor, a HSP90 (heat shock protein 90) inhibitor, an IAP (inhibitorof apoptosis) inhibitor, an mTOR (mechanistic target of rapamycin)inhibitor, a microtubule stabilizer, a microtubule destabilizer, anauristatin, a dolastatin, a MetAP (methionine aminopeptidase), a CRM1(chromosomal maintenance 1) inhibitor, a DPPIV (dipeptidyl peptidase IV)inhibitor, a proteasome inhibitor, an inhibitor of a phosphoryl transferreaction in mitochondria, a protein synthesis inhibitor, a kinaseinhibitor, a CDK2 (cyclin-dependent kinase 2) inhibitor, a CDK9(cyclin-dependent kinase 9) inhibitor, a kinesin inhibitor, an HDAC(histone deacetylase) inhibitor, a DNA damaging agent, a DNA alkylatingagent, a DNA intercalator, a DNA minor groove binder, a RNA polymeraseinhibitor, a topoisomerase inhibitor, or a DHFR (dihydrofolatereductase) inhibitor.

In one embodiment, the linker is chosen from a cleavable linker, anon-cleavable linker, a hydrophilic linker, a procharged linker, or adicarboxylic acid based linker.

In some embodiments, the ADCs are compounds according to structuralformula (I):

[D-L-XY]_(n)-Ab or salts thereof, where each “D” represents,independently of the others, a cytotoxic and/or cytostatic agent(“drug”); each “L” represents, independently of the others, a linker;“Ab” represents a MBM described herein; each “XY” represents a linkageformed between a functional group Rx on the linker and a “complementary”functional group R^(y) on the antibody, and n represents the number ofdrugs linked to, or drug-to-antibody ratio (DAR), of the ADC.

Some embodiments of the various antibodies (Ab) that can comprise theADCs include the various embodiments of MBMs described above.

In some embodiments of the ADCs and/or salts of structural formula (I),each D is the same and/or each L is the same.

Some embodiments of cytotoxic and/or cytostatic agents (D) and linkers(L) that can comprise the ADCs of the disclosure, as well as the numberof cytotoxic and/or cytostatic agents linked to the ADCs, are describedin more detail below.

7.10.1. Cytotoxic and/or Cytostatic Agents

The cytotoxic and/or cytostatic agents can be any agents known toinhibit the growth and/or replication of and/or kill cells, and inparticular cancer and/or tumor cells. Numerous agents having cytotoxicand/or cytostatic properties are known in the literature. Non-limitingexamples of classes of cytotoxic and/or cytostatic agents include, byway of example and not limitation, radionuclides, alkylating agents,topoisomerase I inhibitors, topoisomerase II inhibitors, DNAintercalating agents (e.g., groove binding agents such as minor groovebinders), RNA/DNA antimetabolites, cell cycle modulators, kinaseinhibitors, protein synthesis inhibitors, histone deacetylaseinhibitors, mitochondria inhibitors, and antimitotic agents.

Specific non-limiting examples of agents within certain of these variousclasses are provided below.

Alkylatinq Agents: asaley ((L-Leucine,N-[N-acetyl-4-[bis-(2-chloroethyl)amino]-DL-phenylalanyl]-, ethylester;NSC 167780; CAS Registry No. 3577897)); AZQ((1,4-cyclohexadiene-1,4-dicarbamic acid,2,5-bis(1-aziridinyl)-3,6-dioxo-, diethyl ester; NSC 182986; CASRegistry No. 57998682)); BCNU ((N,N′-Bis(2-chloroethyl)-N-nitrosourea;NSC 409962; CAS Registry No. 154938)); busulfan (1,4-butanedioldimethanesulfonate; NSC 750; CAS Registry No. 55981);(carboxyphthalato)platinum (NSC 27164; CAS Registry No. 65296813); CBDCA((cis-(1,1-cyclobutanedicarboxylato)diammineplatinum(II)); NSC 241240;CAS Registry No. 41575944)); CCNU((N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea; NSC 79037; CAS RegistryNo. 13010474)); CHIP (iproplatin; NSC 256927); chlorambucil (NSC 3088;CAS Registry No. 305033); chlorozotocin ((2-[[[(2-chloroethyl)nitrosoamino]carbonyl]amino]-2-deoxy-D-glucopyranose; NSC 178248; CASRegistry No. 54749905)); cis-platinum (cisplatin; NSC 119875; CASRegistry No. 15663271); clomesone (NSC 338947; CAS Registry No.88343720); cyanomorpholinodoxorubicin (NCS 357704; CAS Registry No.88254073); cyclodisone (NSC 348948; CAS Registry No. 99591738);dianhydrogalactitol (5,6-diepoxydulcitol; NSC 132313; CAS Registry No.23261203); fluorodopan((5-[(2-chloroethyl)-(2-fluoroethyl)amino]-6-methyl-uracil; NSC 73754;CAS Registry No. 834913); hepsulfam (NSC 329680; CAS Registry No.96892578); hycanthone (NSC 142982; CAS Registry No. 23255938); melphalan(NSC 8806; CAS Registry No. 3223072); methyl CCNU((1-(2-chloroethyl)-3-(trans-4-methylcyclohexane)-1-nitrosourea; NSC95441; 13909096); mitomycin C (NSC 26980; CAS Registry No. 50077);mitozolamide (NSC 353451; CAS Registry No. 85622953); nitrogen mustard((bis(2-chloroethyl)methylamine hydrochloride; NSC 762; CAS Registry No.55867); PCNU((1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea; NSC 95466;CAS Registry No. 13909029)); piperazine alkylator((1-(2-chloroethyl)-4-(3-chloropropyl)-piperazine dihydrochloride; NSC344007)); piperazinedione (NSC 135758; CAS Registry No. 41109802);pipobroman ((N,N-bis(3-bromopropionyl) piperazine; NSC 25154; CASRegistry No. 54911)); porfiromycin (N-methylmitomycin C; NSC 56410; CASRegistry No. 801525); spirohydantoin mustard (NSC 172112; CAS RegistryNo. 56605164); teroxirone (triglycidylisocyanurate; NSC 296934; CASRegistry No. 2451629); tetraplatin (NSC 363812; CAS Registry No.62816982); thio-tepa (N,N′,N″-tri-1,2-ethanediylthio phosphoramide; NSC6396; CAS Registry No. 52244); triethylenemelamine (NSC 9706; CASRegistry No. 51183); uracil nitrogen mustard (desmethyldopan; NSC 34462;CAS Registry No. 66751); Yoshi-864 ((bis(3-mesyloxy propyl)aminehydrochloride; NSC 102627; CAS Registry No. 3458228).

Topoisomerase I Inhibitors: camptothecin (NSC 94600; CAS Registry No.7689-03-4); various camptothecin derivatives and analogs (for example,NSC 100880, NSC 603071, NSC 107124, NSC 643833, NSC 629971, NSC 295500,NSC 249910, NSC 606985, NSC 74028, NSC 176323, NSC 295501, NSC 606172,NSC 606173, NSC 610458, NSC 618939, NSC 610457, NSC 610459, NSC 606499,NSC 610456, NSC 364830, and NSC 606497); morpholinisoxorubicin (NSC354646; CAS Registry No. 89196043); SN-38 (NSC 673596; CAS Registry No.86639-52-3).

Topoisomerase II Inhibitors: doxorubicin (NSC 123127; CAS Registry No.25316409); amonafide (benzisoquinolinedione; NSC 308847; CAS RegistryNo. 69408817); m-AMSA((4′-(9-acridinylamino)-3′-methoxymethanesulfonanilide; NSC 249992; CASRegistry No. 51264143)); anthrapyrazole derivative ((NSC 355644);etoposide (VP-16; NSC 141540; CAS Registry No. 33419420);pyrazoloacridine ((pyrazolo[3,4,5-kl]acridine-2(6H)-propanamine,9-methoxy-N, N-dimethyl-5-nitro-, monomethanesulfonate; NSC 366140; CASRegistry No. 99009219); bisantrene hydrochloride (NSC 337766; CASRegistry No. 71439684); daunorubicin (NSC 821151; CAS Registry No.23541506); deoxydoxorubicin (NSC 267469; CAS Registry No. 63950061);mitoxantrone (NSC 301739; CAS Registry No. 70476823); menogaril (NSC269148; CAS Registry No. 71628961); N,N-dibenzyl daunomycin (NSC 268242;CAS Registry No. 70878512); oxanthrazole (NSC 349174; CAS Registry No.105118125); rubidazone (NSC 164011; CAS Registry No. 36508711);teniposide (VM-26; NSC 122819; CAS Registry No. 29767202).

DNA Intercalating Agents: anthramycin (CAS Registry No. 4803274);chicamycin A (CAS Registry No. 89675376); tomaymycin (CAS Registry No.35050556); DC-81 (CAS Registry No. 81307246); sibiromycin (CAS RegistryNo. 12684332); pyrrolobenzodiazepine derivative (CAS Registry No.945490095); SGD-1882((S)-2-(4-aminophenyl)-7-methoxy-8-(3-4(S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-[1,2-a][1,4]diazepin-8-yl)oxy)propox-y)-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one); SG2000 (SJG-136;(11a′S,11a′S)-8,8′-(propane-1,3-diylbis(oxy))bis(7-methoxy-2-methylene-2,3--dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one); NSC694501; CAS Registry No. 232931576).

RNA/DNA Antimetabolites: L-alanosine (NSC 153353; CAS Registry No.59163416); 5-azacytidine (NSC 102816; CAS Registry No. 320672);5-fluorouracil (NSC 19893; CAS Registry No. 51218); acivicin (NSC163501; CAS Registry No. 42228922); aminopterin derivativeN42-chloro-5-[[(2,4-diamino-5-methyl-6-quinazolinyl)methyl]amino]benzoyl-]L-aspartic acid (NSC 132483); aminopterin derivativeN44-[[(2,4-diamino-5-ethyl-6-quinazolinyl)methyl]amino]benzoyl]L-asparti-c acid (NSC 184692); aminopterin derivativeN42-chloro-4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]L-asparticacid monohydrate (NSC 134033); an antifo((N^(α)-(4-amino-4-deoxypteroyl)-N⁷-hemiphthaloyl-L-ornithin-e; NSC623017)); Baker's soluble antifol (NSC 139105; CAS Registry No.41191042); dichlorallyl lawsone((2-(3,3-dichloroallyl)-3-hydroxy-1,4-naphthoquinone; NSC 126771; CASRegistry No. 36417160); brequinar (NSC 368390; CAS Registry No.96201886); ftorafur ((pro-drug; 5-fluoro-1-(tetrahydro-2-furyl)-uracil;NSC 148958; CAS Registry No. 37076689); 5,6-dihydro-5-azacytidine (NSC264880; CAS Registry No. 62402317); methotrexate (NSC 740; CAS RegistryNo. 59052); methotrexate derivative(N-[[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-1-naphthalenyl]car-bonyl]L-glutamic acid; NSC 174121); PALA((N-(phosphonoacetyl)-L-aspartate; NSC 224131; CAS Registry No.603425565); pyrazofurin (NSC 143095; CAS Registry No. 30868305);trimetrexate (NSC 352122; CAS Registry No. 82952645).

DNA Antimetabolites: 3-HP (NSC 95678; CAS Registry No. 3814797);2′-deoxy-5-fluorouridine (NSC 27640; CAS Registry No. 50919); 5-HP (NSC107392; CAS Registry No. 19494894); a-TGDR (a-2′-deoxy-6-thioguanosine;NSC 71851 CAS Registry No. 2133815); aphidicolin glycinate (NSC 303812;CAS Registry No. 92802822); ara C (cytosine arabinoside; NSC 63878; CASRegistry No. 69749); 5-aza-2′-deoxycytidine (NSC 127716; CAS RegistryNo. 2353335); β-TGDR (β-2′-deoxy-6-thioguanosine; NSC 71261; CASRegistry No. 789617); cyclocytidine (NSC 145668; CAS Registry No.10212256); guanazole (NSC 1895; CAS Registry No. 1455772); hydroxyurea(NSC 32065; CAS Registry No. 127071); inosine glycodialdehyde (NSC118994; CAS Registry No. 23590990); macbecin II (NSC 330500; CASRegistry No. 73341738); pyrazoloimidazole (NSC 51143; CAS Registry No.6714290); thioguanine (NSC 752; CAS Registry No. 154427); thiopurine(NSC 755; CAS Registry No. 50442).

Cell Cycle Modulators: silibinin (CAS Registry No. 22888-70-6);epigallocatechin gallate (EGCG; CAS Registry No. 989515); procyanidinderivatives (e.g., procyanidin A1 [CAS Registry No. 103883030],procyanidin B1 [CAS Registry No. 20315257], procyanidin B4 [CAS RegistryNo. 29106512], arecatannin B1 [CAS Registry No. 79763283]); isoflavones(e.g., genistein [4′, 5,7-trihydroxyisoflavone; CAS Registry No.446720], daidzein [4′, 7-dihydroxyisoflavone, CAS Registry No. 486668];indole-3-carbinol (CAS Registry No. 700061); quercetin (NSC 9219; CASRegistry No. 117395); estramustine (NSC 89201; CAS Registry No.2998574); nocodazole (CAS Registry No. 31430189); podophyllotoxin (CASRegistry No. 518285); vinorelbine tartrate (NSC 608210; CAS Registry No.125317397); cryptophycin (NSC 667642; CAS Registry No. 124689652).

Kinase Inhibitors: afatinib (CAS Registry No. 850140726); axitinib (CASRegistry No. 319460850); ARRY-438162 (binimetinib) (CAS Registry No.606143899); bosutinib (CAS Registry No. 380843754); cabozantinib (CASRegistry No. 1140909483); ceritinib (CAS Registry No. 1032900256);crizotinib (CAS Registry No. 877399525); dabrafenib (CAS Registry No.1195765457); dasatinib (NSC 732517; CAS Registry No. 302962498);erlotinib (NSC 718781; CAS Registry No. 183319699); everolimus (NSC733504; CAS Registry No. 159351696); fostamatinib (NSC 745942; CASRegistry No. 901119355); gefitinib (NSC 715055; CAS Registry No.184475352); ibrutinib (CAS Registry No. 936563961); imatinib (NSC716051; CAS Registry No. 220127571); lapatinib (CAS Registry No.388082788); lenvatinib (CAS Registry No. 857890392); mubritinib (CAS366017096); nilotinib (CAS Registry No. 923288953); nintedanib (CASRegistry No. 656247175); palbociclib (CAS Registry No. 571190302);pazopanib (NSC 737754; CAS Registry No. 635702646); pegaptanib (CASRegistry No. 222716861); ponatinib (CAS Registry No. 1114544318);rapamycin (NSC 226080; CAS Registry No. 53123889); regorafenib (CASRegistry No. 755037037); AP 23573 (ridaforolimus) (CAS Registry No.572924540); INCB018424 (ruxolitinib) (CAS Registry No. 1092939177);ARRY-142886 (selumetinib) (NSC 741078; CAS Registry No. 606143-52-6);sirolimus (NSC 226080; CAS Registry No. 53123889); sorafenib (NSC724772; CAS Registry No. 475207591); sunitinib (NSC 736511; CAS RegistryNo. 341031547); tofacitinib (CAS Registry No. 477600752); temsirolimus(NSC 683864; CAS Registry No. 163635043); trametinib (CAS Registry No.871700173); vandetanib (CAS Registry No. 443913733); vemurafenib (CASRegistry No. 918504651); SU6656 (CAS Registry No. 330161870); CEP-701(lesaurtinib) (CAS Registry No. 111358884); XL019 (CAS Registry No.945755566); PD-325901 (CAS Registry No. 391210109); PD-98059 (CASRegistry No. 167869218); ATP-competitive TORC1/TORC2 inhibitorsincluding PI-103 (CAS Registry No. 371935749), PP242 (CAS Registry No.1092351671), PP30 (CAS Registry No. 1092788094), Torin 1 (CAS RegistryNo. 1222998368), LY294002 (CAS Registry No. 154447366), XL-147 (CASRegistry No. 934526893), CAL-120 (CAS Registry No. 870281348), ETP-45658(CAS Registry No. 1198357797), PX 866 (CAS Registry No. SO₂₆₃₂₆₆₈),GDC-0941 (CAS Registry No. 957054307), BGT226 (CAS Registry No.1245537681), BEZ235 (CAS Registry No. 915019657), XL-765 (CAS RegistryNo. 934493762).

Protein Synthesis Inhibitors: acriflavine (CAS Registry No. 65589700);amikacin (NSC 177001; CAS Registry No. 39831555); arbekacin (CASRegistry No. 51025855); astromicin (CAS Registry No. 55779061);azithromycin (NSC 643732; CAS Registry No. 83905015); bekanamycin (CASRegistry No. 4696768); chlortetracycline (NSC 13252; CAS Registry No.64722); clarithromycin (NSC 643733; CAS Registry No. 81103119);clindamycin (CAS Registry No. 18323449); clomocycline (CAS Registry No.1181540); cycloheximide (CAS Registry No. 66819); dactinomycin (NSC3053; CAS Registry No. 50760); dalfopristin (CAS Registry No.112362502); demeclocycline (CAS Registry No. 127333); dibekacin (CASRegistry No. 34493986); dihydrostreptomycin (CAS Registry No. 128461);dirithromycin (CAS Registry No. 62013041); doxycycline (CAS Registry No.17086281); emetine (NSC 33669; CAS Registry No. 483181); erythromycin(NSC 55929; CAS Registry No. 114078); flurithromycin (CAS Registry No.83664208); framycetin (neomycin B; CAS Registry No. 119040); gentamycin(NSC 82261; CAS Registry No. 1403663); glycylcyclines, such astigecycline (CAS Registry No. 220620097); hygromycin B (CAS Registry No.31282049); isepamicin (CAS Registry No. 67814760); josamycin (NSC122223; CAS Registry No. 16846245); kanamycin (CAS Registry No.8063078); ketolides such as telithromycin (CAS Registry No. 191114484),cethromycin (CAS Registry No. 205110481), and solithromycin (CASRegistry No. 760981837); lincomycin (CAS Registry No. 154212);lymecycline (CAS Registry No. 992212); meclocycline (NSC 78502; CASRegistry No. 2013583); metacycline (rondomycin; NSC 356463; CAS RegistryNo. 914001); midecamycin (CAS Registry No. 35457808); minocycline (NSC141993; CAS Registry No. 10118908); miocamycin (CAS Registry No.55881077); neomycin (CAS Registry No. 119040); netilmicin (CAS RegistryNo. 56391561); oleandomycin (CAS Registry No. 3922905); oxazolidinones,such as eperezolid (CAS Registry No. 165800044), linezolid (CAS RegistryNo. 165800033), posizolid (CAS Registry No. 252260029), radezolid (CASRegistry No. 869884786), ranbezolid (CAS Registry No. 392659380),sutezolid (CAS Registry No. 168828588), tedizolid (CAS Registry No.856867555); oxytetracycline (NSC 9169; CAS Registry No. 2058460);paromomycin (CAS Registry No. 7542372); penimepicycline (CAS RegistryNo. 4599604); peptidyl transferase inhibitors, e.g., chloramphenicol(NSC 3069; CAS Registry No. 56757) and derivatives such as azidamfenicol(CAS Registry No. 13838089), florfenicol (CAS Registry No. 73231342),and thiamphenicol (CAS Registry No. 15318453), and pleuromutilins suchas retapamulin (CAS Registry No. 224452668), tiamulin (CAS Registry No.55297955), valnemulin (CAS Registry No. 101312929); pirlimycin (CASRegistry No. 79548735); puromycin (NSC 3055; CAS Registry No. 53792);quinupristin (CAS Registry No. 120138503); ribostamycin (CAS RegistryNo. 53797356); rokitamycin (CAS Registry No. 74014510); rolitetracycline(CAS Registry No. 751973); roxithromycin (CAS Registry No. 80214831);sisomicin (CAS Registry No. 32385118); spectinomycin (CAS Registry No.1695778); spiramycin (CAS Registry No. 8025818); streptogramins such aspristinamycin (CAS Registry No. 270076603), quinupristin/dalfopristin(CAS Registry No. 126602899), and virginiamycin (CAS Registry No.11006761); streptomycin (CAS Registry No. 57921); tetracycline (NSC108579; CAS Registry No. 60548); tobramycin (CAS Registry No. 32986564);troleandomycin (CAS Registry No. 2751099); tylosin (CAS Registry No.1401690); verdamicin (CAS Registry No. 49863481).

Histone Deacetylase Inhibitors: abexinostat (CAS Registry No.783355602); belinostat (NSC 726630; CAS Registry No. 414864009);chidamide (CAS Registry No. 743420022); entinostat (CAS Registry No.209783802); givinostat (CAS Registry No. 732302997); mocetinostat (CASRegistry No. 726169739); panobinostat (CAS Registry No. 404950807);quisinostat (CAS Registry No. 875320299); resminostat (CAS Registry No.864814880); romidepsin (CAS Registry No. 128517077); sulforaphane (CASRegistry No. 4478937); thioureidobutyronitrile (Kevetrin™; CAS RegistryNo. 6659890); valproic acid (NSC 93819; CAS Registry No. 99661);vorinostat (NSC 701852; CAS Registry No. 149647789); ACY-1215(rocilinostat; CAS Registry No. 1316214524); CUDC-101 (CAS Registry No.1012054599); CHR-2845 (tefinostat; CAS Registry No. 914382608); CHR-3996(CAS Registry No. 1235859138); 4SC-202 (CAS Registry No. 910462430);CG200745 (CAS Registry No. 936221339); SB939 (pracinostat; CAS RegistryNo. 929016966).

Mitochondria Inhibitors: pancratistatin (NSC 349156; CAS Registry No.96281311); rhodamine-123 (CAS Registry No. 63669709); edelfosine (NSC324368; CAS Registry No. 70641519); d-alpha-tocopherol succinate (NSC173849; CAS Registry No. 4345033); compound 11β (CAS Registry No.865070377); aspirin (NSC 406186; CAS Registry No. 50782); ellipticine(CAS Registry No. 519233); berberine (CAS Registry No. 633658);cerulenin (CAS Registry No. 17397896); GX₀₁₅-070 (Obatoclax®; 1H-Indole,2-(2-(2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-;NSC 729280; CAS Registry No. 803712676); celastrol (tripterine; CASRegistry No. 34157830); metformin (NSC 91485; CAS Registry No. 1115704);Brilliant green (NSC 5011; CAS Registry No. 633034); ME-344 (CASRegistry No. 1374524556).

Antimitotic Agents: allocolchicine (NSC 406042); auristatins, such asMMAE (monomethyl auristatin E; CAS Registry No. 474645-27-7) and MMAF(monomethyl auristatin F; CAS Registry No. 745017-94-1; halichondrin B(NSC 609395); colchicine (NSC 757; CAS Registry No. 64868); cholchicinederivative (N-benzoyl-deacetyl benzamide; NSC 33410; CAS Registry No.63989753); dolastatin 10 (NSC 376128; CAS Registry No 110417-88-4);maytansine (NSC 153858; CAS Registry No. 35846-53-8); rhozoxin (NSC332598; CAS Registry No. 90996546); taxol (NSC 125973; CAS Registry No.33069624); taxol derivative ((2′-N-[3-(dimethylamino)propyl]glutaramatetaxol; NSC 608832); thiocolchicine (3-demethylthiocolchicine; NSC361792); trityl cysteine (NSC 49842; CAS Registry No. 2799077);vinblastine sulfate (NSC 49842; CAS Registry No. 143679); vincristinesulfate (NSC 67574; CAS Registry No. 2068782).

Any of these agents that include or that can be modified to include asite of attachment to a MBM can be included in the ADCs disclosedherein.

In some embodiments, the cytotoxic and/or cytostatic agent is anantimitotic agent.

In some embodiments, the cytotoxic and/or cytostatic agent is anauristatin, for example, monomethyl auristatin E (“MMAE:) or monomethylauristatin F (”MMAF″).

7.10.2. ADC Linkers

In the ADCs of the disclosure, the cytotoxic and/or cytostatic agentsare linked to the MBM by way of ADC linkers. The ADC linker linking acytotoxic and/or cytostatic agent to the MBM of an ADC can be short,long, hydrophobic, hydrophilic, flexible or rigid, or can be composed ofsegments that each independently have one or more of the above-mentionedproperties such that the linker can include segments having differentproperties. The linkers can be polyvalent such that they covalently linkmore than one agent to a single site on the MBM, or monovalent such thatcovalently they link a single agent to a single site on the MBM.

As will be appreciated by a skilled artisan, the ADC linkers linkcytotoxic and/or cytostatic agents to the MBM by forming a covalentlinkage to the cytotoxic and/or cytostatic agent at one location and acovalent linkage to the MBM at another. The covalent linkages are formedby reaction between functional groups on the ADC linker and functionalgroups on the agents and MBM. As used herein, the expression “ADClinker” is intended to include (i) unconjugated forms of the ADC linkerthat include a functional group capable of covalently linking the ADClinker to a cytotoxic and/or cytostatic agent and a functional groupcapable of covalently linking the ADC linker to a MBM; (ii) partiallyconjugated forms of the ADC linker that include a functional groupcapable of covalently linking the ADC linker to a MBM and that iscovalently linked to a cytotoxic and/or cytostatic agent, or vice versa;and (iii) fully conjugated forms of the ADC linker that are covalentlylinked to both a cytotoxic and/or cytostatic agent and a MBM. In someembodiments of ADC linkers and ADCs of the disclosure, as well assynthons used to conjugate linker-agents to MBMs, moieties comprisingthe functional groups on the ADC linker and covalent linkages formedbetween the ADC linker and MBM are specifically illustrated as R_(x) andXY, respectively.

The ADC linkers are, but need not be, chemically stable to conditionsoutside the cell, and can be designed to cleave, immolate and/orotherwise specifically degrade inside the cell. Alternatively, ADClinkers that are not designed to specifically cleave or degrade insidethe cell can be used. Choice of stable versus unstable ADC linker candepend upon the toxicity of the cytotoxic and/or cytostatic agent. Foragents that are toxic to normal cells, stable linkers can be used.Agents that are selective or targeted and have lower toxicity to normalcells can be utilized, as chemical stability of the ADC linker to theextracellular milieu is less important. A wide variety of ADC linkersuseful for linking drugs to MBMs in the context of ADCs are known. Anyof these ADC linkers, as well as other ADC linkers, can be used to linkthe cytotoxic and/or cytostatic agents to the MBM of the ADCs of thedisclosure.

Exemplary polyvalent ADC linkers that can be used to link many cytotoxicand/or cytostatic agents to a single MBM molecule are described, forexample, in WO 2009/073445; WO 2010/068795; WO 2010/138719; WO2011/120053; WO 2011/171020; WO 2013/096901; WO 2014/008375; WO2014/093379; WO 2014/093394; WO 2014/093640. For example, the Fleximerlinker technology developed by Mersana et al. has the potential toenable high-DAR ADCs with good physicochemical properties. As shownbelow, the Mersana technology is based on incorporating drug moleculesinto a solubilizing poly-acetal backbone via a sequence of ester bonds.The methodology renders highly-loaded ADCs (DAR up to 20) whilemaintaining good physicochemical properties.

Additional examples of dendritic type linkers can be found in US2006/116422; US 2005/271615; de Groot et al., 2003, Angew. Chem. Int.Ed. 42:4490-4494; Amir et al., 2003, Angew. Chem. Int. Ed. 42:4494-4499;Shamis et al., 2004, J. Am. Chem. Soc. 126:1726-1731; Sun et al., 2002,Bioorganic & Medicinal Chemistry Letters 12:2213-2215; Sun et al., 2003,Bioorganic & Medicinal Chemistry 11:1761-1768; King et al., 2002,Tetrahedron Letters 43:1987-1990.

Exemplary monovalent ADC linkers that can be used are described, forexample, in Nolting, 2013, Antibody-Drug Conjugates, Methods inMolecular Biology 1045:71-100; Kitson et al., 2013,CROs—MOs-Chemica—ggi-Chemistry Today 31(4):30-38; Ducry et al., 2010,Bioconjugate Chem. 21:5-13; Zhao et al., 2011, J. Med. Chem.54:3606-3623; U.S. Pat. Nos. 7,223,837; 8,568,728; 8,535,678; andWO2004010957.

By way of example and not limitation, some cleavable and noncleavableADC linkers that can be included in the ADCs are described below.

7.10.2.1. Cleavable ADC Linkers

In certain embodiments, the ADC linker selected is cleavable in vivo.Cleavable ADC linkers can include chemically or enzymatically unstableor degradable linkages. Cleavable ADC linkers generally rely onprocesses inside the cell to liberate the drug, such as reduction in thecytoplasm, exposure to acidic conditions in the lysosome, or cleavage byspecific proteases or other enzymes within the cell. Cleavable ADClinkers generally incorporate one or more chemical bonds that are eitherchemically or enzymatically cleavable while the remainder of the ADClinker is noncleavable. In certain embodiments, an ADC linker comprisesa chemically labile group such as hydrazone and/or disulfide groups.Linkers comprising chemically labile groups exploit differentialproperties between the plasma and some cytoplasmic compartments. Theintracellular conditions to facilitate drug release for hydrazonecontaining ADC linkers are the acidic environment of endosomes andlysosomes, while the disulfide containing ADC linkers are reduced in thecytosol, which contains high thiol concentrations, e.g., glutathione. Incertain embodiments, the plasma stability of an ADC linker comprising achemically labile group can be increased by introducing steric hindranceusing substituents near the chemically labile group.

Acid-labile groups, such as hydrazone, remain intact during systemiccirculation in the blood's neutral pH environment (pH 7.3-7.5) andundergo hydrolysis and release the drug once the ADC is internalizedinto mildly acidic endosomal (pH 5.0-6.5) and lysosomal (pH 4.5-5.0)compartments of the cell. This pH dependent release mechanism has beenassociated with nonspecific release of the drug. To increase thestability of the hydrazone group of the ADC linker, the ADC linker canbe varied by chemical modification, e.g., substitution, allowing tuningto achieve more efficient release in the lysosome with a minimized lossin circulation.

Hydrazone-containing ADC linkers can contain additional cleavage sites,such as additional acid-labile cleavage sites and/or enzymaticallylabile cleavage sites. ADCs including exemplary hydrazone-containing ADClinkers include the following structures:

where D and Ab represent the cytotoxic and/or cytostatic agent (drug)and Ab, respectively, and n represents the number of drug-ADC linkerslinked to the MBM. In certain ADC linkers such as linker (Ig), the ADClinker comprises two cleavable groups--a disulfide and a hydrazonemoiety. For such ADC linkers, effective release of the unmodified freedrug requires acidic pH or disulfide reduction and acidic pH. Linkerssuch as (1h) and (Ii) have been shown to be effective with a singlehydrazone cleavage site.

Additional ADC linkers which remain intact during systemic circulationand undergo hydrolysis and release the drug when the ADC is internalizedinto acidic cellular compartments include carbonates. Such ADC linkerscan be useful in cases where the cytotoxic and/or cytostatic agent canbe covalently attached through an oxygen.

Other acid-labile groups that can be included in ADC linkers includecis-aconityl-containing ADC linkers. cis-Aconityl chemistry uses acarboxylic acid juxtaposed to an amide bond to accelerate amidehydrolysis under acidic conditions.

Cleavable ADC linkers can also include a disulfide group. Disulfides arethermodynamically stable at physiological pH and are designed to releasethe drug upon internalization inside cells, where the cytosol provides asignificantly more reducing environment compared to the extracellularenvironment. Scission of disulfide bonds generally requires the presenceof a cytoplasmic thiol cofactor, such as (reduced) glutathione (GSH),such that disulfide-containing ADC linkers are reasonably stable incirculation, selectively releasing the drug in the cytosol. Theintracellular enzyme protein disulfide isomerase, or similar enzymescapable of cleaving disulfide bonds, can also contribute to thepreferential cleavage of disulfide bonds inside cells. GSH is reportedto be present in cells in the concentration range of 0.5-10 mM comparedwith a significantly lower concentration of GSH or cysteine, the mostabundant low-molecular weight thiol, in circulation at approximately 5Tumor cells, where irregular blood flow leads to a hypoxic state, resultin enhanced activity of reductive enzymes and therefore even higherglutathione concentrations. In certain embodiments, the in vivostability of a disulfide-containing ADC linker can be enhanced bychemical modification of the ADC linker, e.g., use of steric hindranceadjacent to the disulfide bond.

ADCs including exemplary disulfide-containing ADC linkers include thefollowing structures:

where D and Ab represent the drug and MBM, respectively, n representsthe number of drug-ADC linkers linked to the MBM and R is independentlyselected at each occurrence from hydrogen or alkyl, for example. Incertain embodiments, increasing steric hindrance adjacent to thedisulfide bond increases the stability of the ADC linker. Structuressuch as (lj) and (ll) show increased in vivo stability when one or moreR groups is selected from a lower alkyl such as methyl.

Another type of cleavable ADC linker that can be used is an ADC linkerthat is specifically cleaved by an enzyme. Such ADC linkers aretypically peptide-based or include peptidic regions that act assubstrates for enzymes. Peptide based ADC linkers tend to be more stablein plasma and extracellular milieu than chemically labile ADC linkers.Peptide bonds generally have good serum stability, as lysosomalproteolytic enzymes have very low activity in blood due to endogenousinhibitors and the unfavorably high pH value of blood compared tolysosomes. Release of a drug from a MBM occurs specifically due to theaction of lysosomal proteases, e.g., cathepsin and plasmin. Theseproteases can be present at elevated levels in certain tumor cells.

In exemplary embodiments, the cleavable peptide is selected fromtetrapeptides such as Gly-Phe-Leu-Gly, (SEQ ID NO: 553), Ala-Leu-Ala-Leu(SEQ ID NO: 554) or dipeptides such as Val-Cit, Val-Ala, Met-(D)Lys,Asn-(D)Lys, Val-(D)Asp, Phe-Lys, Ile-Val, Asp-Val, His-Val,NorVal-(D)Asp, Ala-(D)Asp 5, Met-Lys, Asn-Lys, Ile-Pro, Me3Lys-Pro,PhenylGly-(D)Lys, Met-(D)Lys, Asn-(D)Lys, Pro-(D)Lys, Met-(D)Lys,Asn-(D)Lys, AM Met-(D)Lys, Asn-(D)Lys, AW Met-(D)Lys, and Asn-(D)Lys. Incertain embodiments, dipeptides can be selected over longer polypeptidesdue to hydrophobicity of the longer peptides.

A variety of dipeptide-based cleavable ADC linkers useful for linkingdrugs such as doxorubicin, mitomycin, camptothecin,pyrrolobenzodiazepine, tallysomycin and auristatin/auristatin familymembers to MBMs have been described (see, Dubowchik et al., 1998, J.Org. Chem. 67:1866-1872; Dubowchik et al., 1998, Bioorg. Med. Chem.Lett. 8(21):3341-3346; Walker et al., 2002, Bioorg. Med. Chem. Lett.12:217-219; Walker et al., 2004, Bioorg. Med. Chem. Lett. 14:4323-4327;Sutherland et al., 2013, Blood 122: 1455-1463; and Francisco et al.,2003, Blood 102:1458-1465). All of these dipeptide ADC linkers, ormodified versions of these dipeptide ADC linkers, can be used in theADCs of the disclosure. Other dipeptide ADC linkers that can be usedinclude those found in ADCs such as Seattle Genetics' BrentuximabVendotin SGN-35 (Adcetris™), Seattle Genetics SGN-75 (anti-CD-70,Val-Cit-monomethyl auristatin F(MMAF), Seattle Genetics SGN-CD33A(anti-CD-33, Val-Ala-(SGD-1882)), Celldex Therapeutics glembatumumab(CDX-011) (anti-NMB, Val-Cit-monomethyl auristatin E (MMAE), and CytogenPSMA-ADC (PSMA-ADC-1301) (anti-PSMA, Val-Cit-MMAE).

Enzymatically cleavable ADC linkers can include a self-immolative spacerto spatially separate the drug from the site of enzymatic cleavage. Thedirect attachment of a drug to a peptide ADC linker can result inproteolytic release of an amino acid adduct of the drug, therebyimpairing its activity. The use of a self-immolative spacer allows forthe elimination of the fully active, chemically unmodified drug uponamide bond hydrolysis.

One self-immolative spacer is the bifunctional para-aminobenzyl alcoholgroup, which is linked to the peptide through the amino group, formingan amide bond, while amine containing drugs can be attached throughcarbamate functionalities to the benzylic hydroxyl group of the ADClinker (PABC). The resulting prodrugs are activated uponprotease-mediated cleavage, leading to a 1,6-elimination reactionreleasing the unmodified drug, carbon dioxide, and remnants of the ADClinker group. The following scheme depicts the fragmentation ofp-amidobenzyl ether and release of the drug:

where X-D represents the unmodified drug.

Heterocyclic variants of this self-immolative group have also beendescribed. See for example, U.S. Pat. No. 7,989,434.

In some embodiments, the enzymatically cleavable ADC linker is aβ-glucuronic acid-based ADC linker. Facile release of the drug can berealized through cleavage of the β-glucuronide glycosidic bond by thelysosomal enzyme β-glucuronidase. This enzyme is present abundantlywithin lysosomes and is overexpressed in some tumor types, while theenzyme activity outside cells is low. β-Glucuronic acid-based ADClinkers can be used to circumvent the tendency of an ADC to undergoaggregation due to the hydrophilic nature of β-glucuronides. In someembodiments, β-glucuronic acid-based ADC linkers can be used as ADClinkers for ADCs linked to hydrophobic drugs. The following schemedepicts the release of the drug from and ADC containing a β-glucuronicacid-based ADC linker:

A variety of cleavable β-glucuronic acid-based ADC linkers useful forlinking drugs such as auristatins, camptothecin and doxorubicinanalogues, CBI minor-groove binders, and psymberin to MBMs have beendescribed (see, Nolting, Chapter 5 “Linker Technology in Antibody-DrugConjugates,” In: Antibody-Drug Conjugates: Methods in Molecular Biology,vol. 1045, pp. 71-100, Laurent Ducry (Ed.), Springer Science & BusinessMedica, LLC, 2013; Jeffrey et al., 2006, Bioconjug. Chem. 17:831-840;Jeffrey et al., 2007, Bioorg. Med. Chem. Lett. 17:2278-2280; and Jianget al., 2005, J. Am. Chem. Soc. 127:11254-11255). All of theseβ-glucuronic acid-based ADC linkers can be used in the ADCs of thedisclosure.

Additionally, cytotoxic and/or cytostatic agents containing a phenolgroup can be covalently bonded to an ADC linker through the phenolicoxygen. One such ADC linker, described in WO 2007/089149, relies on amethodology in which a diamino-ethane “SpaceLink” is used in conjunctionwith traditional “PABO”-based self-immolative groups to deliver phenols.The cleavage of the ADC linker is depicted schematically below, where Drepresents a cytotoxic and/or cytostatic agent having a phenolichydroxyl group.

Cleavable ADC linkers can include noncleavable portions or segments,and/or cleavable segments or portions can be included in an otherwisenon-cleavable ADC linker to render it cleavable. By way of example only,polyethylene glycol (PEG) and related polymers can include cleavablegroups in the polymer backbone. For example, a polyethylene glycol orpolymer ADC linker can include one or more cleavable groups such as adisulfide, a hydrazone or a dipeptide.

Other degradable linkages that can be included in ADC linkers includeester linkages formed by the reaction of PEG carboxylic acids oractivated PEG carboxylic acids with alcohol groups on a biologicallyactive agent, where such ester groups generally hydrolyze underphysiological conditions to release the biologically active agent.Hydrolytically degradable linkages include, but are not limited to,carbonate linkages; imine linkages resulting from reaction of an amineand an aldehyde; phosphate ester linkages formed by reacting an alcoholwith a phosphate group; acetal linkages that are the reaction product ofan aldehyde and an alcohol; orthoester linkages that are the reactionproduct of a formate and an alcohol; and oligonucleotide linkages formedby a phosphoramidite group, including but not limited to, at the end ofa polymer, and a 5′ hydroxyl group of an oligonucleotide.

In certain embodiments, the ADC linker comprises an enzymaticallycleavable peptide moiety, for example, an ADC linker comprisingstructural formula (IVa) or (IVb):

or a salt thereof, where: peptide represents a peptide (illustrated C→Nand not showing the carboxy and amino “termini”) cleavable by alysosomal enzyme; T represents a polymer comprising one or more ethyleneglycol units or an alkylene chain, or combinations thereof; R^(a) isselected from hydrogen, alkyl, sulfonate and methyl sulfonate; p is aninteger ranging from 0 to 5; q is 0 or 1; x is 0 or 1; y is 0 or 1;

represents the point of attachment of the ADC linker to a cytotoxicand/or cytostatic agent; and * represents the point of attachment to theremainder of the ADC linker.

In certain embodiments, the peptide is selected from a tripeptide or adipeptide. In particular embodiments, the dipeptide is selected from:Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit;Val-Glu; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp;Ala-Val; Val-Ala; Phe-Lys; Val-Lys; Ala-Lys; Phe-Cit; Leu-Cit; Ile-Cit;Phe-Arg; and Trp-Cit. In certain embodiments, the dipeptide is selectedfrom: Cit-Val; and Ala-Val.

Specific exemplary embodiments of ADC linkers according to structuralformula (IVa) that can be included in the ADCs include the ADC linkersillustrated below (as illustrated, the ADC linkers include a groupsuitable for covalently linking the ADC linker to a MBM):

Specific exemplary embodiments of ADC linkers according to structuralformula (IVb) that can be included in the ADCs include the ADC linkersillustrated below (as illustrated, the ADC linkers include a groupsuitable for covalently linking the ADC linker to a MBM):

In certain embodiments, the ADC linker comprises an enzymaticallycleavable peptide moiety, for example, an ADC linker comprisingstructural formula (IVc) or (IVd):

or a salt thereof, where: peptide represents a peptide (illustrated C→Nand not showing the carboxy and amino “termini”) cleavable by alysosomal enzyme; T represents a polymer comprising one or more ethyleneglycol units or an alkylene chain, or combinations thereof; R^(a) sselected from hydrogen, alkyl, sulfonate and methyl sulfonate; p is aninteger ranging from 0 to 5; q is 0 or 1; x is 0 or 1; y is 0 or 1; .x

represents the point of attachment of the ADC linker to a cytotoxicand/or cytostatic agent; and * represents the point of attachment to theremainder of the ADC linker.

Specific exemplary embodiments of ADC linkers according to structuralformula (IVc) that can be included in the ADCs include the ADC linkersillustrated below (as illustrated, the ADC linkers include a groupsuitable for covalently linking the ADC linker to a MBM):

Specific exemplary embodiments of ADC linkers according to structuralformula (IVd) that can be included in the ADCs include the ADC linkersillustrated below (as illustrated, the ADC linkers include a groupsuitable for covalently linking the ADC linker to a MBM):

In certain embodiments, the ADC linker comprising structural formula(IVa), (IVb), (IVc), or (IVd) further comprises a carbonate moietycleavable by exposure to an acidic medium. In particular embodiments,the ADC linker is attached through an oxygen to a cytotoxic and/orcytostatic agent.

7.10.2.2. Non-Cleavable Linkers

Although cleavable ADC linkers can provide certain advantages, the ADClinkers comprising the ADCs need not be cleavable. For noncleavable ADClinkers, the release of drug does not depend on the differentialproperties between the plasma and some cytoplasmic compartments. Therelease of the drug is postulated to occur after internalization of theADC via antigen-mediated endocytosis and delivery to lysosomalcompartment, where the MBM is degraded to the level of amino acidsthrough intracellular proteolytic degradation. This process releases adrug derivative, which is formed by the drug, the ADC linker, and theamino acid residue to which the ADC linker was covalently attached. Theamino acid drug metabolites from conjugates with noncleavable ADClinkers are more hydrophilic and generally less membrane permeable,which leads to less bystander effects and less nonspecific toxicitiescompared to conjugates with a cleavable ADC linker. In general, ADCswith noncleavable ADC linkers have greater stability in circulation thanADCs with cleavable ADC linkers. Non-cleavable ADC linkers can bealkylene chains, or can be polymeric in nature, such as, for example,based upon polyalkylene glycol polymers, amide polymers, or can includesegments of alkylene chains, polyalkylene glocols and/or amide polymers.

A variety of non-cleavable ADC linkers used to link drugs to MBMs havebeen described. See, Jeffrey et al., 2006, Bioconjug. Chem. 17; 831-840;Jeffrey et al., 2007, Bioorg. Med. Chem. Lett. 17:2278-2280; and Jianget al., 2005, J. Am. Chem. Soc. 127:11254-11255. All of these ADClinkers can be included in the ADCs of the disclosure.

In certain embodiments, the ADC linker is non-cleavable in vivo, forexample an ADC linker according to structural formula (VIa), (VIb),(VIc) or (VId) (as illustrated, the ADC linkers include a group suitablefor covalently linking the ADC linker to a MBM:

or salts thereof, where: R^(a) is selected from hydrogen, alkyl,sulfonate and methyl sulfonate; R^(x) is a moiety including a functionalgroup capable of covalently linking the ADC linker to a MBM; and

represents the point of attachment of the ADC linker to a cytotoxicand/or cytostatic agent.

Specific exemplary embodiments of ADC linkers according to structuralformula (VIa)-(VId) that can be included in the ADCs include the ADClinkers illustrated below (as illustrated, the ADC linkers include agroup suitable for covalently linking the ADC linker to a MBM, and

represents the point of attachment to a cytotoxic and/or cytostaticagent):

7.10.2.3. Groups Used to Attach Linkers to MBMs

A variety of groups can be used to attach ADC linker-drug synthons toMBMs (e.g., TBMs) to yield ADCs. Attachment groups can be electrophilicin nature and include: maleimide groups, activated disulfides, activeesters such as NHS esters and HOBt esters, haloformates, acid halides,alkyl and benzyl halides such as haloacetamides. As discussed below,there are also emerging technologies related to “self-stabilizing”maleimides and “bridging disulfides” that can be used in accordance withthe disclosure. The specific group used will depend, in part, on thesite of attachment to the MBM.

One example of a “self-stabilizing” maleimide group that hydrolyzesspontaneously under MBM conjugation conditions to give an ADC specieswith improved stability is depicted in the schematic below. SeeUS20130309256 A1; also Lyon et al., Nature Biotech published online,doi:10.1038/nbt.2968.

Normal System:

SGN MaIDPR (maleimido dipropylamino) system:

Polytherics has disclosed a method for bridging a pair of sulfhydrylgroups derived from reduction of a native hinge disulfide bond. See,Badescu et al., 2014, Bioconjugate Chem. 25:1124-1136. The reaction isdepicted in the schematic below. An advantage of this methodology is theability to synthesize enriched DAR4 ADCs by full reduction of IgGs (togive 4 pairs of sulfhydryls) followed by reaction with 4 equivalents ofthe alkylating agent. ADCs containing “bridged disulfides” haveincreased stability.

Similarly, as depicted below, a maleimide derivative (1, below) that iscapable of bridging a pair of sulfhydryl groups has been developed. SeeWO2013/085925.

7.10.2.4. ADC Linker Selection Considerations

As is known by skilled artisans, the ADC linker selected for aparticular ADC can be influenced by a variety of factors, including butnot limited to, the site of attachment to the MBM (e.g., lys, cys orother amino acid residues), structural constraints of the drugpharmacophore and the lipophilicity of the drug. The specific ADC linkerselected for an ADC should seek to balance these different factors forthe specific MBM/drug combination. For a review of the factors that areinfluenced by choice of ADC linkers in ADCs, see Nolting, Chapter 5“Linker Technology in Antibody-Drug Conjugates,” In: Antibody-DrugConjugates: Methods in Molecular Biology, vol. 1045, pp. 71-100, LaurentDucry (Ed.), Springer Science & Business Medica, LLC, 2013.

For example, ADCs have been observed to effect killing of bystanderantigen-negative cells present in the vicinity of the antigen-positivetumor cells. The mechanism of bystander cell killing by ADCs hasindicated that metabolic products formed during intracellular processingof the ADCs may play a role. Neutral cytotoxic metabolites generated bymetabolism of the ADCs in antigen-positive cells appear to play a rolein bystander cell killing while charged metabolites can be preventedfrom diffusing across the membrane into the medium and therefore cannotaffect bystander killing. In certain embodiments, the ADC linker isselected to attenuate the bystander killing effect caused by cellularmetabolites of the ADC. In certain embodiments, the ADC linker isselected to increase the bystander killing effect.

The properties of the ADC linker can also impact aggregation of the ADCunder conditions of use and/or storage. Typically, ADCs reported in theliterature contain no more than 3-4 drug molecules per antibody molecule(see, e.g., Chari, 2008, Acc Chem Res 41:98-107). Attempts to obtainhigher drug-to-antibody ratios (“DAR”) often failed, particularly ifboth the drug and the ADC linker were hydrophobic, due to aggregation ofthe ADC (King et al., 2002, J Med Chem 45:4336-4343; Hollander et al.,2008, Bioconjugate Chem 19:358-361; Burke et al., 2009 Bioconjugate Chem20:1242-1250). In many instances, DARs higher than 3-4 could bebeneficial as a means of increasing potency. In instances where thecytotoxic and/or cytostatic agent is hydrophobic in nature, it can bedesirable to select ADC linkers that are relatively hydrophilic as ameans of reducing ADC aggregation, especially in instances where DARSgreater than 3-4 are desired. Thus, in certain embodiments, the ADClinker incorporates chemical moieties that reduce aggregation of theADCs during storage and/or use. An ADC linker can incorporate polar orhydrophilic groups such as charged groups or groups that become chargedunder physiological pH to reduce the aggregation of the ADCs. Forexample, an ADC linker can incorporate charged groups such as salts orgroups that deprotonate, e.g., carboxylates, or protonate, e.g., amines,at physiological pH.

Exemplary polyvalent ADC linkers that have been reported to yield DARsas high as 20 that can be used to link numerous cytotoxic and/orcytostatic agents to a MBM are described in WO 2009/073445; WO2010/068795; WO 2010/138719; WO 2011/120053; WO 2011/171020; WO2013/096901; WO 2014/008375; WO 2014/093379; WO 2014/093394; WO2014/093640.

In particular embodiments, the aggregation of the ADCs during storage oruse is less than about 10% as determined by size-exclusionchromatography (SEC). In particular embodiments, the aggregation of theADCs during storage or use is less than 10%, such as less than about 5%,less than about 4%, less than about 3%, less than about 2%, less thanabout 1%, less than about 0.5%, less than about 0.1%, or even lower, asdetermined by size-exclusion chromatography (SEC).

7.10.3. Methods of Making ADCs

The ADCs can be synthesized using chemistries that are well-known. Thechemistries selected will depend upon, among other things, the identityof the cytotoxic and/or cytostatic agent(s), the ADC linker and thegroups used to attach ADC linker to the MBM. Generally, ADCs accordingto formula (I) can be prepared according to the following scheme:

D−L−R^(x)+Ab−R^(y)→[D−L−XY] _(n) −Ab   (I)

where D, L, Ab, XY and n are as previously defined, and Rx and RYrepresent complementary groups capable of forming a covalent linkageswith one another, as discussed above.

The identities of groups R^(x) and R^(y) will depend upon the chemistryused to link synthon D-L-R^(x) to the MBM. Generally, the chemistry usedshould not alter the integrity of the MBM, for example its ability tobind its target. In some cases, the binding properties of the conjugatedantibody will closely resemble those of the unconjugated MBM. A varietyof chemistries and techniques for conjugating molecules to biologicalmolecules and in particular to immunoglobulins, whose components aretypically building blocks of the MBMs of the disclosure, are well-known.See, e.g., Amon et al., “Monoclonal Antibodies For Immunotargeting OfDrugs In Cancer Therapy,” in: Monoclonal Antibodies And Cancer Therapy,Reisfeld et al. Eds., Alan R. Liss, Inc., 1985; Hellstrom et al.,“Antibodies For Drug Delivery,” in: Controlled Drug Delivery, Robinsonet al. Eds., Marcel Dekker, Inc., 2nd Ed. 1987; Thorpe, “AntibodyCarriers Of Cytotoxic Agents In Cancer Therapy: A Review,” in:Monoclonal Antibodies ‘84: Biological And Clinical Applications,Pinchera et al., Eds., 1985; “Analysis, Results, and Future Prospectiveof the Therapeutic Use of Radiolabeled Antibody In Cancer Therapy,” in:Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.,Eds., Academic Press, 1985; Thorpe et al., 1982, Immunol. Rev.62:119-58; PCT publication WO 89/12624. Any of these chemistries can beused to link the synthons to a MBM.

A number of functional groups Rx and chemistries useful for linkingsynthons to accessible lysine residues are known, and include by way ofexample and not limitation NHS-esters and isothiocyanates.

A number of functional groups Rx and chemistries useful for linkingsynthons to accessible free sulfhydryl groups of cysteine residues areknown, and include by way of example and not limitation haloacetyls andmaleimides.

However, conjugation chemistries are not limited to available side chaingroups. Side chains such as amines can be converted to other usefulgroups, such as hydroxyls, by linking an appropriate small molecule tothe amine. This strategy can be used to increase the number of availablelinking sites on the antibody by conjugating multifunctional smallmolecules to side chains of accessible amino acid residues of the MBM.Functional groups Rx suitable for covalently linking the synthons tothese “converted” functional groups are then included in the synthons.

The MBM can also be engineered to include amino acid residues forconjugation. An approach for engineering MBMs to include non-geneticallyencoded amino acid residues useful for conjugating drugs in the contextof ADCs is described by Axup et al., 2012, Proc Natl Acad Sci USA.109(40):16101-16106, as are chemistries and functional group useful forlinking synthons to the non-encoded amino acids.

Typically, the synthons are linked to the side chains of amino acidresidues of the MBM, including, for example, the primary amino group ofaccessible lysine residues or the sulfhydryl group of accessiblecysteine residues. Free sulfhydryl groups can be obtained by reducinginterchain disulfide bonds.

For linkages where R^(y) is a sulfhydryl group (for example, when R^(x)is a maleimide), the MBM is generally first fully or partially reducedto disrupt interchain disulfide bridges between cysteine residues.

Cysteine residues that do not participate in disulfide bridges can beengineered into a MBM by modification of one or more codons. Reducingthese unpaired cysteines yields a sulfhydryl group suitable forconjugation. In some embodiments, MBMs are engineered to introduce oneor more cysteine residues as sites for conjugation to a drug moiety(see, Junutula, et al, 2008, Nat Biotechnol, 26:925-932).

Sites for cysteine substitution can be selected in a constant region toprovide stable and homogeneous conjugates. A MBM can have, for example,two or more cysteine substitutions, and these substitutions can be usedin combination with other modification and conjugation methods asdescribed herein. Methods for inserting cysteine at specific locationsof an antibody are known, see, e.g., Lyons et al., 1990, Protein Eng.,3:703-708, WO 2011/005481, WO2014/124316, WO 2015/138615. In certainembodiments, a MBM comprises a substitution of one or more amino acidswith cysteine on a constant region selected from positions 117, 119,121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 205, 207,246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334,335, 337, 344, 355, 360, 375, 382, 390, 392, 398, 400 and 422 of a heavychain, where the positions are numbered according to the EU system. Insome embodiments, a MBM comprises a substitution of one or more aminoacids with cysteine on a constant region selected from positions 107,108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168,169, 170, 182, 183, 197, 199, and 203 of a light chain, where thepositions are numbered according to the EU system, and where the lightchain is a human kappa light chain. In certain embodiments a MBMcomprises a combination of substitution of two or more amino acids withcysteine on a constant region, where the combinations comprisesubstitutions at positions 375 of a heavy chain, position 152 of a heavychain, position 360 of a heavy chain, or position 107 of a light chainand where the positions are numbered according to the EU system. Incertain embodiments a MBM comprises a substitution of one amino acidwith cysteine on a constant region where the substitution is position375 of a heavy chain, position 152 of a heavy chain, position 360 of aheavy chain, position 107 of a light chain, position 165 of a lightchain or position 159 of a light chain and where the positions arenumbered according to the EU system, and where the light chain is akappa chain.

In particular embodiments, a MBM comprises a combination of substitutionof two amino acids with cysteine on a constant regions, where the MBMcomprises cysteines at positions 152 and 375 of a heavy chain, where thepositions are numbered according to the EU system.

In other particular embodiments, a MBM comprises a substitution of oneamino acid with cysteine at position 360 of a heavy chain, where thepositions are numbered according to the EU system.

In other particular embodiments, a MBM comprises a substitution of oneamino acid with cysteine at position 107 of a light chain, where thepositions are numbered according to the EU system, and where the lightchain is a kappa chain.

Other positions for incorporating engineered cysteines can include, byway of example and not limitation, positions S112C, S113C, A114C, S1150,A1760, 5180C, S252C, V286C, V292C, S357C, A359C, S398C, S428C (Kabatnumbering) on the human IgG₁ heavy chain and positions V1100, S114C,S121C, S1270, S1680, V205C (Kabat numbering) on the human Ig kappa lightchain (see, e.g., U.S. Pat. No. 7,521,541, U.S. Pat. No. 7,855,275 andU.S. Pat. No. 8,455,622).

MBMs useful in ADCs disclosed herein can additionally or alternativelybe modified to introduce one or more other reactive amino acids (otherthan cysteine), including Pcl, pyrrolysine, peptide tags (such as S6, A1and ybbR tags), and non-natural amino acids, in place of at least oneamino acid of the native sequence, thus providing a reactive site on theMBM for conjugation to a drug moiety. For example, MBMs can be modifiedto incorporate Pcl or pyrrolysine (W. Ou et al., 2011, PNAS,108(26):10437-10442; WO2014124258) or unnatural amino acids (Axup, etal., 2012, PNAS, 109:16101-16106; for review, see C.C. Liu and P.G.Schultz, 2010, Annu Rev Biochem 79:413-444; Kim, et al., 2013, Curr OpinChem Biol. 17:412-419) as sites for conjugation to a drug. Similarly,peptide tags for enzymatic conjugation methods can be introduced into aMBM (see, Strop et al. 2013, Chem Biol. 20(2):161-7; Rabuka, 2010, CurrOpin Chem Biol. 14(6):790-6; Rabuka, et al., 2012, Nat Protoc.7(6):1052-67). One other example is the use of 4’-phosphopantetheinyltransferases (PPTase) for the conjugation of Coenzyme A analogs(WO2013184514). Such modified or engineered MBMs can be conjugated withpayloads or linker-payload combinations according to methods known.

As will appreciated by skilled artisans, the number of agents (e.g.,cytotoxic and/or cytostatic agents) linked to a MBM molecule can vary,such that a collection of ADCs can be heterogeneous in nature, wheresome MBMs contain one linked agent, some two, some three, etc. (and somenone). The degree of heterogeneity will depend upon, among other things,the chemistries used for linking the agents. For example, where the MBMsare reduced to yield sulfhydryl groups for attachment, heterogeneousmixtures of MBMs having zero, 2, 4, 6 or 8 linked agents per moleculeare often produced. Furthermore, by limiting the molar ratio ofattachment compound, MBMs having zero, 1, 2, 3, 4, 5, 6, 7 or 8 linkedagents per molecule are often produced. Thus, it will be understood thatdepending upon context, stated drug MBM ratios (DTRs) can be averagesfor a collection of MBMs. For example, “DTR4” can refer to an ADCpreparation that has not been subjected to purification to isolatespecific DTR peaks and can comprise a heterogeneous mixture of ADCmolecules having different numbers of cytostatic and/or cytotoxic agentsattached per MBM (e.g., 0, 2, 4, 6, 8 agents per MBM), but has anaverage drug-to-MBM ratio of 4. Similarly, in some embodiments, “DTR2”refers to a heterogeneous ADC preparation in which the averagedrug-to-MBM ratio is 2.

When enriched preparations are desired, MBMs having defined numbers oflinked agents (e.g., cytotoxic and/or cytostatic agents) can be obtainedvia purification of heterogeneous mixtures, for example, via columnchromatography, e.g., hydrophobic interaction chromatography.

Purity can be assessed by a variety of known methods. As an example, anADC preparation can be analyzed via HPLC or other chromatography and thepurity assessed by analyzing areas under the curves of the resultantpeaks.

7.11. Pharmaceutical Compositions

The MBMs (e.g., TBMs) (as well as their conjugates; references to MBMsin this disclosure also refers to conjugates comprising the MBMs, suchas ADCs, unless the context dictates otherwise) can be formulated aspharmaceutical compositions comprising the MBMs, for example containingone or more pharmaceutically acceptable excipients or carriers. Toprepare pharmaceutical or sterile compositions comprising the MBMs ofthe present disclosure a MBM preparation can be combined with one ormore pharmaceutically acceptable excipient or carrier.

For example, formulations of MBMs can be prepared by mixing MBMs withphysiologically acceptable carriers, excipients, or stabilizers in theform of, e.g., lyophilized powders, slurries, aqueous solutions,lotions, or suspensions (see, e.g., Hardman et al., 2001, Goodman andGilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, NewYork, N.Y.; Gennaro, 2000, Remington: The Science and Practice ofPharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, etal. (eds.),1993, Pharmaceutical Dosage Forms: General Medications,Marcel Dekker, NY; Lieberman, et al. (eds.), 1990, Pharmaceutical DosageForms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.), 1990,Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weinerand Kotkoskie, 2000, Excipient Toxicity and Safety, Marcel Dekker, Inc.,New York, N.Y.).

Selecting an administration regimen for a MBM depends on severalfactors, including the serum or tissue turnover rate of the MBM, thelevel of symptoms, the immunogenicity of the MBM, and the accessibilityof the target cells. In certain embodiments, an administration regimenmaximizes the amount of MBM delivered to the subject consistent with anacceptable level of side effects. Accordingly, the amount of MBMdelivered depends in part on the particular MBM and the severity of thecondition being treated. Guidance in selecting appropriate doses ofantibodies and small molecules are available (see, e.g., Wawrzynczak,1996, Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK;Kresina (ed.), 1991, Monoclonal Antibodies, Cytokines and Arthritis,Marcel Dekker, New York, N.Y.; Bach (ed.), 1993, Monoclonal Antibodiesand Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York,N.Y.; Baert et al., 2003, New Engl. J. Med. 348:601-608; Milgrom et al.,1999, New Engl. J. Med. 341:1966-1973; Slamon et al., 2001, New Engl. J.Med. 344:783-792; Beniaminovitz et al., 2000, New Engl. J. Med.342:613-619; Ghosh et al., 2003, New Engl. J. Med. 348:24-32; Lipsky etal., 2000, New Engl. J. Med. 343:1594-1602).

Determination of the appropriate dose is made by the clinician, e.g.,using parameters or factors known or suspected in the art to affecttreatment or predicted to affect treatment. Generally, the dose beginswith an amount somewhat less than the optimum dose and it is increasedby small increments thereafter until the desired or optimum effect isachieved relative to any negative side effects. Important diagnosticmeasures include those of symptoms of, e.g., the inflammation or levelof inflammatory cytokines produced.

Actual dosage levels of the MBMs in the pharmaceutical compositions ofthe present disclosure can be varied so as to obtain an amount of theMBM which is effective to achieve the desired therapeutic response for aparticular subject, composition, and mode of administration, withoutbeing toxic to the subject. The selected dosage level will depend upon avariety of pharmacokinetic factors including the activity of theparticular MBM, the route of administration, the time of administration,the rate of excretion of the particular MBM being employed, the durationof the treatment, other agents (e.g., active agents such as therapeuticdrugs or compounds and/or inert materials used as carriers) incombination with the particular MBM employed, the age, sex, weight,condition, general health and prior medical history of the subject beingtreated, and like factors known in the medical arts.

Compositions comprising the MBMs can be provided by continuous infusion,or by doses at intervals of, e.g., one day, one week, or 1-7 times perweek. Doses can be provided intravenously, subcutaneously, topically,orally, nasally, rectally, intramuscular, intracerebrally, or byinhalation. An exemplary dose protocol is one involving the maximal doseor dose frequency that avoids significant undesirable side effects.

An effective amount for a particular subject can vary depending onfactors such as the condition being treated, the overall health of thesubject, the method route and dose of administration and the severity ofside effects (see, e.g., Maynard, et al. (1996) A Handbook of SOPs forGood Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001)Good Laboratory and Good Clinical Practice, Urch Publ., London, UK).

The route of administration can be by, e.g., topical or cutaneousapplication, injection or infusion by intravenous, intraperitoneal,intracerebral, intramuscular, intraocular, intraarterial,intracerebrospinal, intralesional, or by sustained release systems or animplant (see, e.g., Sidman et al., 1983, Biopolymers 22:547-556; Langeret al., 1981, J. Biomed. Mater. Res. 15:167-277; Langer, 1982, Chem.Tech. 12:98-105; Epstein et al., 1985, Proc. Natl. Acad. Sci. USA82:3688-3692; Hwang et al., 1980, Proc. Natl. Acad. Sci. USA77:4030-4034; U.S. Pat. Nos. 6,350,466 and 6,316,024). Where necessary,the composition can also include a solubilizing agent and a localanesthetic such as lidocaine to ease pain at the site of the injection.In addition, pulmonary administration can also be employed, e.g., by useof an inhaler or nebulizer, and formulation with an aerosolizing agent.See, e.g., U.S. Pat. Nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272,5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos.WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903.

A composition of the present disclosure can also be administered via oneor more routes of administration using one or more of a variety of knownmethods. As will be appreciated by a skilled artisan, the route and/ormode of administration will vary depending upon the desired results.Selected routes of administration for MBMs include intravenous,intramuscular, intradermal, intraperitoneal, subcutaneous, spinal orother general routes of administration, for example by injection orinfusion. General administration can represent modes of administrationother than enteral and topical administration, usually by injection, andincludes, without limitation, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, epidural andintrasternal injection and infusion. Alternatively, a composition of thedisclosure can be administered via a non-general route, such as atopical, epidermal or mucosal route of administration, for example,intranasally, orally, vaginally, rectally, sublingually or topically. Inone embodiment, the MBMs is administered by infusion. In anotherembodiment, an MBM is administered subcutaneously.

If the MBMs are administered in a controlled release or sustainedrelease system, a pump can be used to achieve controlled or sustainedrelease (see Langer, supra; Sefton, 1987, CRC Crit. Ref Biomed. Eng.14:20; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N.Engl. J. Med. 321:574). Polymeric materials can be used to achievecontrolled or sustained release of the therapies of the disclosure (see,e.g., Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J., Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105); U.S. Pat. No. 5,679,377; U.S. Pat. No. 5,916,597;U.S. Pat. No. 5,912,015; U.S. Pat. No. 5,989,463; U.S. Pat. No.5,128,326; PCT Publication No. WO 99/15154; and PCT Publication No. WO99/20253. Examples of polymers used in sustained release formulationsinclude, but are not limited to, poly(2-hydroxy ethyl methacrylate),poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinylacetate), poly(methacrylic acid), polyglycolides (PLG), polyanhydrides,poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide,poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides)(PLGA), and polyorthoesters. In one embodiment, the polymer used in asustained release formulation is inert, free of leachable impurities,stable on storage, sterile, and biodegradable. A controlled or sustainedrelease system can be placed in proximity of the prophylactic ortherapeutic target, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)).

Controlled release systems are discussed in the review by Langer (1990,Science 249:1527-1533). Any technique known to one of skill in the artcan be used to produce sustained release formulations comprising one ormore MBMs of the disclosure. See, e.g., U.S. Pat. No. 4,526,938, PCTpublication WO 91/05548, PCT publication WO 96/20698, Ning et al., 1996,Radiotherapy & Oncology 39:179-189, Song et al., 1995, PDA Journal ofPharmaceutical Science & Technology 50:372-397, Cleek et al., 1997, Pro.Intl Symp. Control. Rel. Bioact. Mater. 24:853-854, and Lam et al.,1997, Proc. Intl Symp. Control Rel. Bioact. Mater. 24:759-760.

If the MBMs are administered topically, they can be formulated in theform of an ointment, cream, transdermal patch, lotion, gel, shampoo,spray, aerosol, solution, emulsion, or other form well-known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences andIntroduction to Pharmaceutical Dosage Forms, 19th ed., Mack Pub. Co.,Easton, Pa. (1995). For non-sprayable topical dosage forms, viscous tosemi-solid or solid forms comprising a carrier or one or more excipientscompatible with topical application and having a dynamic viscosity, insome instances, greater than water are typically employed. Suitableformulations include, without limitation, solutions, suspensions,emulsions, creams, ointments, powders, liniments, salves, and the like,which are, if desired, sterilized or mixed with auxiliary agents (e.g.,preservatives, stabilizers, wetting agents, buffers, or salts) forinfluencing various properties, such as, for example, osmotic pressure.Other suitable topical dosage forms include sprayable aerosolpreparations where the active ingredient, in some instances, incombination with a solid or liquid inert carrier, is packaged in amixture with a pressurized volatile (e.g., a gaseous propellant, such asfreon) or in a squeeze bottle. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well-known.

If the compositions comprising the MBMs are administered intranasally,the MBMs can be formulated in an aerosol form, spray, mist or in theform of drops. In particular, prophylactic or therapeutic agents for useaccording to the present disclosure can be conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridges(composed of, e.g., gelatin) for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The MBMs (e.g., TBMs) can be administered in combination therapyregimens, as described in Section 7.13, infra.

In certain embodiments, the MBMs can be formulated to ensure properdistribution in vivo. For example, the blood-brain barrier (BBB)excludes many highly hydrophilic compounds. To ensure that thetherapeutic compounds of the disclosure cross the BBB (if desired), theycan be formulated, for example, in liposomes. For methods ofmanufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548;and 5,399,331. The liposomes can comprise one or more moieties which areselectively transported into specific cells or organs, thus enhancetargeted drug delivery (see, e.g., Ranade, 1989, J. Clin. Pharmacol.29:685). Exemplary targeting moieties include folate or biotin (see,e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa etal., 1988, Biochem. Biophys. Res. Commun. 153:1038); antibodies (Bloemanet al., 1995, FEBS Lett. 357:140; Owais et al., 1995, Antimicrob. AgentsChemother. 39:180); surfactant protein A receptor (Briscoe et al., 1995,Am. J. Physiol. 1233:134); p 120 (Schreier et al., 1994, J. Biol. Chem.269:9090); see also Keinanen and Laukkanen, 1994, FEBS Lett. 346:123;Killion and Fidler,1994, Immunomethods 4:273.

When used in combination therapy, e.g., as described in Section 7.13,infra, a MBM and one or more additional agents can be administered to asubject in the same pharmaceutical composition. Alternatively, the MBMand the additional agent(s) of the combination therapies can beadministered concurrently to a subject in separate pharmaceuticalcompositions.

The therapeutic methods described herein can further comprise carryingout a “companion diagnostic” test whereby a sample from a subject who isa candidate for therapy with a MBM is tested for the expression of BCMAand/or a TAA targeted by the MBM. The companion diagnostic test can beperformed prior to initiating therapy with a MBM and/or during atherapeutic regimen with a MBM to monitor the subject's continuedsuitability for MBM therapy. The agent used in the companion diagnosticcan be the MBM itself or another diagnostic agent, for example a labeledmonospecific antibody against BCMA or the TAA recognized by the MBM or anucleic acid probe to detect TAA RNA. The sample that can be tested in acompanion diagnostic assay can be any sample in which the cells targetedby the MBM can be present, from example a tumor (e.g., a solid tumor)biopsy, lymph, stool, urine, blood or any other bodily fluid that mightcontain circulating tumor cells.

7.12. Therapeutic Indications

The MBMs can be used in the treatment of any disease associated withBCMA expression. For example, a MBM can be used to treat a subject whohas undergone treatment for a disease associated with elevatedexpression of BCMA, where the subject who has undergone treatment forelevated levels of BCMA exhibits a disease associated with elevatedlevels of BCMA.

In one aspect, the disclosure provides a method of inhibiting growth ofa BCMA-expressing tumor cell, comprising contacting the tumor cell witha MBM such that the growth of the tumor cell is inhibited.

In one aspect, the disclosure provides a method of treating and/orpreventing a disease that arises in individuals who areimmunocompromised, comprising administering a MBM of the disclosure. Inparticular, disclosed herein is a method of treating diseases, disordersand conditions associated with expression of BCMA, comprisingadministering a MBM of the disclosure.

In certain aspects, disclosed herein is a method of treating patients atrisk for developing diseases, disorders and conditions associated withexpression of BCMA, comprising administering a MBM of the disclosure.

Thus, the present disclosure provides methods for the treatment orprevention of diseases, disorders and conditions associated withexpression of BCMA comprising administering to a subject in needthereof, a therapeutically effective amount of a MBM of the disclosure.

The present disclosure also provides methods for preventing, treatingand/or managing a disease associated with BCMA-expressing cells (e.g., ahematologic cancer or atypical cancer expressing BCMA), the methodscomprising administering to a subject in need a MBM. In one aspect, thesubject is a human. Non-limiting examples of disorders associated withBCMA-expressing cells include viral or fungal infections, and disordersrelated to mucosal immunity.

7.12.1. Cancer and Cancer-Related Diseases and Disorders

In one aspect, the disclosure provides a method of treating cancer in asubject. The method comprises administering to the subject a MBM suchthat the cancer is treated in the subject. An example of a cancer thatis treatable by the MBM is a cancer associated with expression of BCMA.

In one aspect, the disclosure provides methods for treating a cancerwhere part of the tumor is negative for BCMA and part of the tumor ispositive for BCMA.

In one aspect, the disclosure provides methods for treating a cancerwhere BCMA is expressed on both normal cells and cancers cells, but isexpressed at lower levels on normal cells, using a MBM of thedisclosure. In one embodiment, the method further comprises selecting aMBM that binds with an affinity that allows the MBM to bind and kill thecancer cells expressing BCMA but kill less than 30%, 25%, 20%, 15%, 10%,5% or less of the normal cells expressing BCMA, e.g., as determined byan assay described herein. For example, a killing assay such as flowcytometry based on Cr51 CTL can be used. In one embodiment, the MBM hasan ABM1 that has a binding affinity K_(D) of 10⁻⁴ M to 10⁻⁸ M, e.g.,10⁻⁵ M to 10⁻⁷ M, e.g., 10⁻⁶ M or 10⁻⁷ M, for BCMA.

In one aspect, disclosed herein is a method of treating a proliferativedisease such as a cancer or malignancy or a precancerous condition suchas a myelodysplasia, a myelodysplastic syndrome or a preleukemia,comprising administering a MBM. In one aspect, the cancer is ahematological cancer. Hematological cancer conditions are the types ofcancer such as leukemia and malignant lymphoproliferative conditionsthat affect blood, bone marrow and the lymphatic system. In one aspect,the hematological cancer is a leukemia. An example of a disease ordisorder associated with BCMA is multiple myeloma (also known as MM)(See Claudio et al., Blood. 2002, 100(6):2175-86; and Novak et al.,Blood. 2004, 103(2):689-94). Multiple myeloma, also known as plasma cellmyeloma or Kahler's disease, is a cancer characterized by anaccumulation of abnormal or malignant plasma B-cells in the bone marrow.Frequently, the cancer cells invade adjacent bone, destroying skeletalstructures and resulting in bone pain and fractures. Most cases ofmyeloma also feature the production of a paraprotein (also known as Mproteins or myeloma proteins), which is an abnormal immunoglobulinproduced in excess by the clonal proliferation of the malignant plasmacells. Blood serum paraprotein levels of more than 30g/L is diagnosticof multiple myeloma, according to the diagnostic criteria of theInternational Myeloma Working Group (IMWG) (See Kyle et al. (2009),Leukemia. 23:3-9). Other symptoms or signs of multiple myeloma includereduced kidney function or renal failure, bone lesions, anemia,hypercalcemia, and neurological symptoms.

Other plasma cell proliferative disorders that can be treated by thecompositions and methods described herein include, but are not limitedto, asymptomatic myeloma (smoldering multiple myeloma or indolentmyeloma), monoclonal gammapathy of undetermined significance (MGUS),Waldenstrom's macroglobulinemia, plasmacytomas (e.g., plasma celldyscrasia, solitary myeloma, solitary plasmacytoma, extramedullaryplasmacytoma, and multiple plasmacytoma), systemic amyloid light chainamyloidosis, and POEMS syndrome (also known as Crow-Fukase syndrome,Takatsuki disease, and PEP syndrome).

Another example of a disease or disorder associated with BCMA isHodgkin's lymphoma and non-Hodgkin's lymphoma (See Chiu et al., Blood.2007, 109(2):729-39; He et al., J lmmunol. 2004, 172(5):3268-79).

Hodgkin's lymphoma (HL), also known as Hodgkin's disease, is a cancer ofthe lymphatic system that originates from white blood cells, orlymphocytes. The abnormal cells that comprise the lymphoma are calledReed-Sternberg cells. In Hodgkin's lymphoma, the cancer spreads from onelymph node group to another. Hodgkin's lymphoma can be subclassifiedinto four pathologic subtypes based upon Reed-Sternberg cell morphologyand the cell composition around the Reed-Sternberg cells (as determinedthrough lymph node biopsy): nodular sclerosing HL, mixed-cellularitysubtype, lymphocyte-rich or lymphocytic predominance, lymphocytedepleted. Some Hodgkin's lymphoma can also be nodular lymphocytepredominant Hodgkin's lymphoma, or can be unspecified. Symptoms andsigns of Hodgkin's lymphoma include painless swelling in the lymph nodesin the neck, armpits, or groin, fever, night sweats, weight loss,fatigue, itching, or abdominal pain.

Non-Hodgkin's lymphoma (NHL) comprises a diverse group of blood cancersthat include any kind of lymphoma other than Hodgkin's lymphoma.Subtypes of non-Hodgkin's lymphoma are classified primarily by cellmorphology, chromosomal aberrations, and surface markers. NHL subtypes(or NHL-associated cancers) include B cell lymphomas such as, but notlimited to, Burkitt's lymphoma, B-cell chronic lymphocytic leukemia(B-CLL), B-cell prolymphocytic leukemia (B-PLL), chronic lymphocyticleukemia (CLL), diffuse large B-cell lymphoma (DLBCL) (e.g.,intravascular large B-cell lymphoma and primary mediastinal B-celllymphoma), follicular lymphoma (e.g., follicle center lymphoma,follicular small cleaved cell), hair cell leukemia, high grade B-celllymphoma (Burkitt's like), lymphoplasmacytic lymphoma (Waldenstrom'smacroglublinemia), mantle cell lymphoma, marginal zone B-cell lymphomas(e.g., extranodal marginal zone B-cell lymphoma or mucosa-associatedlymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma,and splenic marginal zone B-cell lymphoma), plasmacytoma/myeloma,precursor B-lymphoblastic leukemia/lymphoma (PB-LBL/L), primary centralnervous system (CNS) lymphoma, primary intraocular lymphoma, smalllymphocytic lymphoma (SLL); and T cell lymphomas, such as, but notlimited to, anaplastic large cell lymphoma (ALCL), adult T-celllymphoma/leukemia (e.g., smoldering, chronic, acute and lymphomatous),angiocentric lymphoma, angioimmunoblastic T-cell lymphoma, cutaneousT-cell lymphomas (e.g., mycosis fungoides, Sezary syndrome, etc.),extranodal natural killer/T-cell lymphoma (nasal-type), enteropathy typeintestinal T-cell lymphoma, large granular lymphocyte leukemia,precursor T-lymphoblastic lymphoma/leukemia (T-LBL/L), T-cell chroniclymphocytic leukemia/prolymphocytic leukemia (T-CLL/PLL), andunspecified peripheral T-cell lymphoma. Symptoms and signs of Hodgkin'slymphoma include painless swelling in the lymph nodes in the neck,armpits, or groin, fever, night sweats, weight loss, fatigue, itching,abdominal pain, coughing, or chest pain.

BCMA expression has also been associated with Waldenstrom'smacroglobulinemia (WM), also known as lymphoplasmacytic lymphoma (LPL).(See Elsawa et al., Blood. 2006, 107(7):2882-8). Waldenstrom'smacroglobulinemia was previously considered to be related to multiplemyeloma, but has more recently been classified as a subtype ofnon-Hodgkin's lymphoma. WM is characterized by uncontrolled B-celllymphocyte proliferation, resulting in anemia and production of excessamounts of paraprotein, or immunoglobulin M (IgM), which thickens theblood and results in hyperviscosity syndrome. Other symptoms or signs ofWM include fever, night sweats, fatigue, anemia, weight loss,lymphadenopathy or splenomegaly, blurred vision, dizziness, nose bleeds,bleeding gums, unusual bruises, renal impairment or failure,amyloidosis, or peripheral neuropathy.

Another example of a disease or disorder associated with BCMA expressionis brain cancer. Specifically, expression of BCMA has been associatedwith astrocytoma or glioblastoma (See Deshayes et al, Oncogene. 2004,23(17):3005-12, Pelekanou et al., PLoS One. 2013, 8(12):e83250).Astrocytomas are tumors that arise from astrocytes, which are a type ofglial cell in the brain. Glioblastoma (also known as glioblastomamultiforme or GBM) is the most malignant form of astrocytoma, and isconsidered the most advanced stage of brain cancer (stage IV). There aretwo variants of glioblastoma: giant cell glioblastoma and gliosarcoma.Other astrocytomas include juvenile pilocytic astrocytoma (JPA),fibrillary astrocytoma, pleomorphic xantroastrocytoma (PXA),desembryoplastic neuroepithelial tumor (DNET), and anaplasticastrocytoma (AA).

Symptoms or signs associated with glioblastoma or astrocytoma includeincreased pressure in the brain, headaches, seizures, memory loss,changes in behavior, loss in movement or sensation on one side of thebody, language dysfunction, cognitive impairments, visual impairment,nausea, vomiting, and weakness in the arms or legs.

Surgical removal of the tumor (or resection) is the standard treatmentfor removal of as much of the glioma as possible without damaging orwith minimal damage to the normal, surrounding brain. Radiation therapyand/or chemotherapy are often used after surgery to suppress and slowrecurrent disease from any remaining cancer cells or satellite lesions.Radiation therapy includes whole brain radiotherapy (conventionalexternal beam radiation), targeted three-dimensional conformalradiotherapy, and targeted radionuclides. Chemotherapeutic agentscommonly used to treat glioblastoma include temozolomide, gefitinib orerlotinib, and cisplatin. Angiogenesis inhibitors, such as Bevacizumab(Avastin®), are also commonly used in combination with chemotherapyand/or radiotherapy.

Supportive treatment is also frequently used to relieve neurologicalsymptoms and improve neurologic function, and is administered incombination any of the cancer therapies described herein. The primarysupportive agents include anticonvulsants and corticosteroids. Thus, thecompositions and methods of the present disclosure can be used incombination with any of the standard or supportive treatments to treat aglioblastoma or astrocytoma.

The present disclosure provides for compositions and methods fortreating cancer. In one aspect, the cancer is a hematologic cancerincluding but not limited to a leukemia or a lymphoma. In one aspect,disclosed herein are methods of treating cancers and malignanciesincluding, but not limited to, e.g., acute leukemias including but notlimited to, e.g., B-cell acute lymphoid leukemia (“BALL”), T-cell acutelymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL); one or morechronic leukemias including but not limited to, e.g., chronicmyelogenous leukemia (CML), chronic lymphocytic leukemia (CLL);additional hematologic cancers or hematologic conditions including, butnot limited to, e.g., B cell prolymphocytic leukemia, blasticplasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse largeB cell lymphoma, Follicular lymphoma, Hairy cell leukemia, small cell-or a large cell-follicular lymphoma, malignant lymphoproliferativeconditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma,multiple myeloma, myelodysplasia and myelodysplastic syndrome,non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendriticcell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” whichare a diverse collection of hematological conditions united byineffective production (or dysplasia) of myeloid blood cells, and thelike. Further diseases associated with BCMA expression include, but arenot limited to, e.g., atypical and/or non-classical cancers,malignancies, precancerous conditions or proliferative diseasesexpressing BCMA.

In some embodiments, a MBM of the disclosure can be used to treat adisease including but not limited to a plasma cell proliferativedisorder, e.g., asymptomatic myeloma (smoldering multiple myeloma orindolent myeloma), monoclonal gammapathy of undetermined significance(MGUS), Waldenstrom's macroglobulinemia, plasmacytomas (e.g., plasmacell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullaryplasmacytoma, and multiple plasmacytoma), systemic amyloid light chainamyloidosis, and POEMS syndrome (also known as Crow-Fukase syndrome,Takatsuki disease, and PEP syndrome).

In some embodiments, a MBM can be used to treat a disease including butnot limited to a cancer, e.g., a cancer described herein, e.g., aprostate cancer (e.g., castrate-resistant or therapy-resistant prostatecancer, or metastatic prostate cancer), pancreatic cancer, or lungcancer.

The present disclosure also provides methods for inhibiting theproliferation or reducing a BCMA-expressing cell population, the methodscomprising contacting a population of cells comprising a BMCA-expressingcell with a MBM of the disclosure. In an aspect, the present disclosureprovides methods for inhibiting the proliferation or reducing thepopulation of cancer cells expressing BCMA, the methods comprisingcontacting the BCMA-expressing cancer cell population with a MBM. In oneaspect, the disclosure provides methods for inhibiting the proliferationor reducing the population of cancer cells expressing BCMA, the methodscomprising contacting the BMCA-expressing cancer cell population with aMBM. In certain aspects, the methods reduce the quantity, number, amountor percentage of cells and/or cancer cells by at least 25%, at least30%, at least 40%, at least 50%, at least 65%, at least 75%, at least85%, at least 95%, or at least 99% in a subject with or an animal modelfor myeloid leukemia or another cancer associated with BCMA-expressingcells relative to a negative control. In one aspect, the subject is ahuman.

The present disclosure provides methods for preventing relapse of cancerassociated with BCMA-expressing cells, the methods comprisingadministering to a subject in need thereof a MBM.

7.12.2. Non-Cancer Related Diseases and Disorders

Non-cancer related diseases and disorders associated with BCMAexpression can also be treated by the compositions and methods disclosedherein. Examples of non-cancer related diseases and disorders associatedwith BCMA expression include, but are not limited to: viral infections;e.g., HIV, fungal infections, e.g., C. neoformans; and autoimmunediseases.

Autoimmune disorders that can be treated with the MBMs of the disclosureinclude systemic lupus erythematosus (SLE), Sjogren's syndrome,scleroderma, rheumatoid arthritis (RA), juvenile idiopathic arthritis,graft versus host disease, dermatomyositis, type I diabetes mellitus,Hashimoto's thyroiditis, Graves's disease, Addison's disease, celiacdisease, disorders related to mucosal immunity, irritable bowel diseases(e.g., Crohn's Disease, ulcerative colitis), pernicious anaemia,pemphigus vulgaris, vitiligo, autoimmune haemolytic anaemia, idiopathicthrombocytopenic purpura, giant cell arteritis, myasthenia gravis,multiple sclerosis (MS) (e.g., relapsing-remitting MS (RRMS)),glomerulonephritis, Goodpasture's syndrome, bullous pemphigoid, colitisulcerosa, Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy, anti-phospholipid syndrome, narcolepsy, sarcoidosis, andWegener's granulomatosis.

In some embodiments, the MBMs of the disclosure are used to treatsystemic lupus erythematosus (SLE).

In some embodiments, the MBMs of the disclosure are used to treatSjogren's syndrome.

In some embodiments, the MBMs of the disclosure are used to treatscleroderma.

In some embodiments, the MBMs of the disclosure are used to treatrheumatoid arthritis (RA).

In some embodiments, the MBMs of the disclosure are used to treatjuvenile idiopathic arthritis.

In some embodiments, the MBMs of the disclosure are used to treat graftversus host disease.

In some embodiments, the MBMs of the disclosure are used to treatdermatomyositis.

In some embodiments, the MBMs of the disclosure are used to treat type Idiabetes mellitus.

In some embodiments, the MBMs of the disclosure are used to treatHashimoto's thyroiditis.

In some embodiments, the MBMs of the disclosure are used to treatGraves's disease.

In some embodiments, the MBMs of the disclosure are used to treatAddison's disease.

In some embodiments, the MBMs of the disclosure are used to treat celiacdisease.

In some embodiments, the MBMs of the disclosure are used to treatCrohn's Disease.

In some embodiments, the MBMs of the disclosure are used to treatpernicious anaemia.

In some embodiments, the MBMs of the disclosure are used to treatpemphigus vulgaris.

In some embodiments, the MBMs of the disclosure are used to treatvitiligo.

In some embodiments, the MBMs of the disclosure are used to treatautoimmune haemolytic anaemia.

In some embodiments, the MBMs of the disclosure are used to treatidiopathic thrombocytopenic purpura.

In some embodiments, the MBMs of the disclosure are used to treat giantcell arteritis.

In some embodiments, the MBMs of the disclosure are used to treatmyasthenia gravis.

In some embodiments, the MBMs of the disclosure are used to treatmultiple sclerosis (MS). In some embodiments, the MS isrelapsing-remitting MS (RRMS).

In some embodiments, the MBMs of the disclosure are used to treatglomerulonephritis.

In some embodiments, the MBMs of the disclosure are used to treatGoodpasture's syndrome.

In some embodiments, the MBMs of the disclosure are used to treatbullous pemphigoid.

In some embodiments, the MBMs of the disclosure are used to treatcolitis ulcerosa.

In some embodiments, the MBMs of the disclosure are used to treatGuillain-Barré syndrome.

In some embodiments, the MBMs of the disclosure are used to treatchronic inflammatory demyelinating polyneuropathy.

In some embodiments, the MBMs of the disclosure are used to treatanti-phospholipid syndrome.

In some embodiments, the MBMs of the disclosure are used to treatnarcolepsy.

In some embodiments, the MBMs of the disclosure are used to treatsarcoidosis.

In some embodiments, the MBMs of the disclosure are used to treatWegener's granulomatosis.

7.13. Combination Therapy

A MBM (e.g., a TBM) of the disclosure can be used in combination withother known agents and therapies. For example, the MBMs can be used intreatment regimens in combination with surgery, chemotherapy,antibodies, radiation, peptide vaccines, steroids, cytoxins, proteasomeinhibitors, immunomodulatory drugs (e.g., IMiDs), BH3 mimetics, cytokinetherapies, stem cell transplant or any combination thereof. Withoutbeing bound by theory, it is believed that one of the advantages of theMBMs of the disclosure is that they can circumvent the need foradministering separate antibodies to a subject suffering from a cancer(e.g., a B cell malignancy). Accordingly, in certain embodiments, theone or more additional agents do not include an antibody (e.g.,rituximab).

For convenience, an agent that is used in combination with a MBM isreferred to herein as an “additional” agent.

Administered “in combination,” as used herein, means that two (or more)different treatments are delivered to the subject during the course ofthe subject's affliction with the disorder, e.g., the two or moretreatments are delivered after the subject has been diagnosed with thedisorder and before the disorder has been cured or eliminated ortreatment has ceased for other reasons. In some embodiments, thedelivery of one treatment is still occurring when the delivery of thesecond begins, so that there is overlap in terms of administration. Thisis sometimes referred to herein as “simultaneous” or “concurrentdelivery”. For example, each therapy can be administered to a subject atthe same time or sequentially in any order at different points in time;however, if not administered at the same time, they should beadministered sufficiently close in time so as to provide the desiredtherapeutic effect.

A MBM and one or more additional agents can be administeredsimultaneously, in the same or in separate compositions, orsequentially. For sequential administration, the MBM can be administeredfirst, and the additional agent can be administered second, or the orderof administration can be reversed.

The MBM and the additional agent(s) can be administered to a subject inany appropriate form and by any suitable route. In some embodiments, theroutes of administration are the same. In other embodiments the routesof administration are different.

In other embodiments, the delivery of one treatment ends before thedelivery of the other treatment begins.

In some embodiments of either case, the treatment is more effectivebecause of combined administration. For example, the second treatment ismore effective, e.g., an equivalent effect is seen with less of thesecond treatment, or the second treatment reduces symptoms to a greaterextent, than would be seen if the second treatment were administered inthe absence of the first treatment, or the analogous situation is seenwith the first treatment. In some embodiments, delivery is such that thereduction in a symptom, or other parameter related to the disorder isgreater than what would be observed with one treatment delivered in theabsence of the other. The effect of the two treatments can be partiallyadditive, wholly additive, or greater than additive. The delivery can besuch that an effect of the first treatment delivered is still detectablewhen the second is delivered.

The MBMs and/or additional agents can be administered during periods ofactive disorder, or during a period of remission or less active disease.A MBM can be administered before the treatment with the additionalagent(s), concurrently with the treatment with the additional agent(s),post-treatment with the additional agent(s), or during remission of thedisorder.

When administered in combination, the MBM and/or the additional agent(s)can be administered in an amount or dose that is higher, lower or thesame than the amount or dosage of each agent used individually, e.g., asa monotherapy.

The additional agent(s) of the combination therapies of the disclosurecan be administered to a subject concurrently. Each therapy can beadministered to a subject together or separately, in any appropriateform and by any suitable route.

The MBM and the additional agent(s) can be administered to a subject bythe same or different routes of administration.

The MBMs and the additional agent(s) can be cyclically administered.Cycling therapy involves the administration of a first therapy (e.g., afirst prophylactic or therapeutic agent) for a period of time, followedby the administration of a second therapy (e.g., a second prophylacticor therapeutic agent) for a period of time, optionally, followed by theadministration of a third therapy (e.g., prophylactic or therapeuticagent) for a period of time and so forth, and repeating this sequentialadministration, i.e., the cycle in order to reduce the development ofresistance to one of the therapies, to avoid or reduce the side effectsof one of the therapies, and/or to improve the efficacy of thetherapies.

In certain instances, the one or more additional agents, are otheranti-cancer agents, anti-allergic agents, anti-nausea agents (oranti-emetics), pain relievers, cytoprotective agents, and combinationsthereof.

In one embodiment, a MBM is administered in combination with ananti-cancer agent (e.g., a chemotherapeutic agent). Exemplarychemotherapeutic agents include an anthracycline (e.g., doxorubicin(e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine,vincristine, vindesine, vinorelbine), an alkylating agent (e.g.,cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), animmune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab,tositumomab, obinutuzumab, ofatumumab, daratumumab, elotuzumab), anantimetabolite (including, e.g., folic acid antagonists, pyrimidineanalogs, purine analogs and adenosine deaminase inhibitors (e.g.,fludarabine)), an mTOR inhibitor, a TNFR glucocorticoid induced TNFRrelated protein (GITR) agonist, a proteasome inhibitor (e.g.,aclacinomycin A, gliotoxin or bortezomib), an immunomodulator such asthalidomide or a thalidomide derivative (e.g., lenalidomide).

General chemotherapeutic agents considered for use in combinationtherapies include anastrozole (Arimidex®), bicalutamide (Casodex®),bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection(Busulfex®), capecitabine (Xeloda®),N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®),carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®),cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®),cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomeinjection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin,polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate(Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine(Tirazone®), topotecan hydrochloride for injection (Hycamptin®),vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine(Navelbine®).

Anti-cancer agents of particular interest for combinations with the MBMsof the present disclosure include: anthracyclines; alkylating agents;antimetabolites; drugs that inhibit either the calcium dependentphosphatase calcineurin or the p70S6 kinase FK506) or inhibit the p70S6kinase; mTOR inhibitors; immunomodulators; vinca alkaloids; proteasomeinhibitors; GITR agonists (e.g., GWN323); protein tyrosine phosphataseinhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinaseinhibitor; a DGK kinase inhibitor; an oncolytic virus; a BH3 mimetic;and cytokine therapies.

A MBM can be administered in combination with one or more anti-canceragents that prevent or slow shedding of an antigen targeted by one ormore of the ABMs of the MBM, thereby reducing the amount of solubleantigen and/or increasing the amount of cell surface bound antigen. Forexample, MBMs can be administered in combination with an ADAM10/17inhibitor (e.g., INCB7839), e.g., to block shedding of an antigenreleased from cancer a cell by ADAM10/17, or in combination with aphospholipase inhibitor, e.g., to block shedding of an antigen releasedfrom a cancer cell by a phospholipase. Also of particular interest forcombinations with the MBMs of the present disclosure are gamma secretasemodulators such as gamma secretase inhibitors (GSIs).

Exemplary alkylating agents include, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®,Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracilnitrogen mustard®, Uracillost®, Uracilmostaza®, Uramustin®,Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®,Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide(Mitoxana0), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman(Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®),triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa(Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®),lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine(DTIC-Dome®). Additional exemplary alkylating agents include, withoutlimitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® andTemodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®);Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard,Alkeran®); Altretamine (also known as hexamethylmelamine (HMM),Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan(Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (alsoknown as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® andPlatinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® andNeosar®); Dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine(HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine(Matulane®); Mechlorethamine (also known as nitrogen mustard, mustineand mechloroethamine hydrochloride, Mustargen®); Streptozocin(Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA,Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®,Revimmune®); and Bendamustine HCI (Treanda®).

Exemplary mTOR inhibitors include, e.g., temsirolimus; ridaforolimus(formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described inPCT Publication No. WO3/064383); everolimus (Afinitor® or RAD001);rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3);emsirolimus,(5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol(AZD8055);2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one(PF04691502, CAS 1013101-36-4); andN241,4-dioxo-44[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-a-aspartylL-serine-(SEQ ID NO: 555), inner salt (SF1126, CAS 936487-67-1), and XL765.

Exemplary immunomodulators include, e.g., afutuzumab (available fromRoche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®);IMIDs (such as thalidomide (Thalomid®), lenalidomide, pomalidomide, andapremilast), actimid (CC4047); and IRX-2 (mixture of human cytokinesincluding interleukin 1, interleukin 2, and interferon y, CAS951209-71-5, available from IRX Therapeutics).

Exemplary anthracyclines include, e.g., doxorubicin (Adriamycin® andRubex®); bleomycin (lenoxane®); daunorubicin (dauorubicin hydrochloride,daunomycin, and rubidomycin hydrochloride, Cerubidine®); daunorubicinliposomal (daunorubicin citrate liposome, DaunoXome®); mitoxantrone(DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®,Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin;ravidomycin; and desacetylravidomycin.

Exemplary vinca alkaloids include, e.g., vinorelbine tartrate(Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®));vinblastine (also known as vinblastine sulfate, vincaleukoblastine andVLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®).

Exemplary proteasome inhibitors include bortezomib (Velcade®);carfilzomib (PX-171-007,(S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-pentanamide);marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib(CEP-18770); andO-Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-R1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912).

Exemplary BH3 mimetics include venetoclax, ABT-737(4-{4-[(4′-Chloro-2-biphenyl)methyl]-1-piperazinyl}-N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)-2-butanyl]amino}-3-nitrophenyl)sulfonyl]benzamideand navitoclax (formerly ABT-263).

Exemplary cytokine therapies include interleukin 2 (IL-2) andinterferon-alpha (IFN-alpha).

In certain aspects, “cocktails” of different chemotherapeutic agents areadministered as the additional agent(s).

In one aspect, the disclosure provides a method for treating subjectsthat have a disease associated with expression of BCMA, comprisingadministering to the subject an effective amount of: (i) a MBM of thedisclosure, and (ii) a gamma secretase inhibitor (GSI).

In one aspect, the disclosure provides a method for treating subjectsthat have undergone treatment for a disease associated with expressionof BCMA, comprising administering to the subject an effective amount of:(i) a MBM of the disclosure, and (ii) a GSI.

In one embodiment, the MBM and the GSI are administered simultaneouslyor sequentially. In one embodiment, the MBM is administered prior to theadministration of the GSI. In one embodiment, the GSI is administeredprior to the administration of the MBM. In one embodiment, the MBM andthe GSI are administered simultaneously.

In one embodiment, the GSI is administered prior to the administrationof the MBM (e.g., GSI is administered 1, 2, 3, 4, or 5 days prior to theadministration of the MBM), optionally where after the administration ofthe GSI and prior to the administration of the MBM, the subject shows anincrease in cell surface BCMA expression levels and/or a decrease insoluble BCMA levels.

In some embodiments, the GSI is a small molecule that reduces theexpression and/or function of gamma secretase, e.g., a small-moleculeGSI disclosed herein. In one embodiment, the GSI is chosen fromLY-450139, PF-5212362, BMS-708163, MK-0752, ELN-318463, BMS-299897,LY-411575, DAPT, BMS-906024, PF-3084014, R04929097, and LY3039478. Inone embodiment, the GSI is chosen from PF-5212362, ELN-318463,BMS-906024, and LY3039478. Exemplary GSIs are disclosed in Takebe etal., Pharmacol Ther. 2014 Feb; 141(2):140-9; and Ran et al., EMBO MolMed. 2017 Jul; 9(7):950-966.

In some embodiments, MK-0752 is administered in combination withdocetaxel. In some embodiments, MK-0752 is administered in combinationwith gemcitabine. In some embodiments, BMS-906024 is administered incombination with chemotherapy.

In some embodiments, the GSI can be a compound of formula (I) or apharmaceutically acceptable salt thereof;

where ring A is aryl or heteroaryl; each of R¹, R², and R⁴ isindependently hydrogen, C₁-C₆ alkyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl, where each C₁-C₆ alkyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl is substituted with 0-6 independent occurrences ofhalogen,—OR^(A), —SR^(A), —C(O)OR^(A), —C(O)N(RA)(RB), —N(RA)(RB),or—C(NR9N(RA)(RB); each R³a, R³b, R⁶a, and R^(5b) is independentlyhydrogen, halogen, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, or heteroaralkyl, where each C₁-C₆ alkyl, C₁-C₆ alkoxy,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl, or heteroaralkyl is substituted with 0-6independent occurrences of halogen, —OH, —OR^(A), —SR^(A), —C(O)OR^(A),—C(O)N(RA)(RB), —N(RA)(RB),or —C(NR9N(RA)(RB); R⁶ is hydrogen, C₁-C₆alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl, where each C₁-C₆ alkyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl, or heteroaralkyl is substituted with 0-6independent occurrences of halogen, —OH, or C₁-C₆ alkoxy; and eachR^(A), R^(B), and Rc is independently hydrogen, C₁-C₆ alkyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, or heteroaralkyl, where each C₁-C₆ alkyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, or heteroaralkyl is substituted with 0-6 independentoccurrences of halogen, —OH, or C₁-C₆ alkoxy.

In some embodiments, ring A is aryl (e.g., phenyl). In some embodiments,R¹ is —CH₃. In some embodiments, each of R² and R⁴ is independentlyhydrogen. In some embodiments, R^(3a) is —CH₃ and Rab is hydrogen. Insome embodiments, R^(5a) is hydrogen and R⁶b is —CH(CH₃)2. In someembodiments, R⁶ is hydrogen.

In a further embodiment, the GSI is a compound described in U.S. Pat.No. 7,468,365. In one embodiment, the GSI is LY-450139, i.e.,semagacestat,(S)-2-hydroxy-3-methyl-N-((S)-1-(((S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)amino)-1-oxopropan-2-yl)butanamide,or a pharmaceutically acceptable salt thereof. In one embodiment, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (II) or apharmaceutically acceptable salt thereof;

where ring B is aryl or heteroaryl; L is a bond, C₁-C₆ alkylene,—S(O)₂-, —C(O)—, —N(R^(E) )(O)C—, or —OC(O)—; each R⁷ is independentlyhalogen, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl, where each C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, or heteroaralkyl is independently substituted with 0-6occurrences of halogen, —OR^(D), —SR^(D), —C(O)OR^(D),—C(O)N(R^(D))(R^(E)), —N(R^(D))(R^(E)), or —C(NR^(F))N(R^(D))(R^(E)); R⁸is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl, where each C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, or heteroaralkyl is substituted with 0-6 independentoccurrences of halogen,—OR^(D), —SR^(D), —C(O)OR^(D),—C(O)N(R^(D))(R^(E)), —N(R^(D))(R^(E)),or —C(NR^(F))N(R^(D))(R^(E));each of R⁹and R¹⁰ is independently hydrogen, halogen, —OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, whereeach C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteroaralkyl is substituted with 0-6independent occurrences of halogen,—OR^(D), —SR° , —C(O)OR^(D),—C(O)N(R^(D))(R^(E) ), —N(R^(D))(R^(E) ),or —C(NR^(I))N(R^(G))(R^(H));each R^(D), R^(E) , and RF is independently hydrogen, C₁-C₆ alkyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl, or heteroaralkyl, where each C C₁-C₆ alkyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl, or heteroaralkyl is substituted with 0-6independent occurrences of halogen, —OH, or C₁-C₆ alkoxy; and n is 0, 1,2, 3, 4, or 5.

In some embodiments, ring B is heteroaryl (e.g., thiofuranyl). In someembodiments, L is —S(O)2. In some embodiments, R⁷ is chloro and n is 1.In some embodiments, R⁸ is — CH₂OH. In some embodiments, each of R⁹ andR¹⁰ is independently —CF₃.

In a further embodiment, the GSI is a compound described in U.S. Pat.No. 7,687,666. In one embodiment, the GSI is PF-5212362, i.e.,begacestat, GSI-953, or(R)-5-chloro-N-(4,4,4-trifluoro-1-hydroxy-3-(trifluoromethyl)butan-2-yl)thiophene-2-sulfonamide,or a pharmaceutically acceptable salt thereof. In one embodiment, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound is a compound of formula(III) or a pharmaceutically acceptable salt thereof:

where each of rings C and D is independently aryl or heteroaryl;

each of R¹¹, R¹², and R¹⁴ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl, where each C₁-C₆ alkyl,C₁-C₆ alkoxy, —S(O)R^(G)—, —S(O)₂R^(G)—, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl is substituted with 0-6 independent occurrences ofhalogen, —OR^(G), —SR^(G), —C(O)OR^(G), —C(O)N(R^(G))(R^(H)),—N(R^(G))(R^(H)),or —C(NR^(I))N(R^(G))(R^(H)); each of R^(13a) andR^(13b) is hydrogen, halogen, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl, or heteroaralkyl, where each C₁-C₆ alkyl, C₁-C₆alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl is substituted with 0-6independent occurrences of halogen, —OR^(G), —SR^(G), —C(O)OR^(G),—C(O)N(R^(G))(R^(H)), —N(R^(G))(R^(H)),or —C(NR^(I))N(R^(G))(R^(H));each R¹⁵ and R¹⁶ is independently halogen, —OH, C₁-C₆ alkyl, C₁-C₆alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl, where each C₁-C₆ alkyl,C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl issubstituted with 0-6 independent occurrences of halogen, —OR^(G),—SR^(G), —C(O)OR^(G), —C(O)N(R^(G))(R^(H)), —N(R^(G))(R^(H)),or—C(NR^(I))N(R^(G))(R^(H)); each R^(G) , RH, and R′ is independentlyhydrogen, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, whereeach C₁-C₆ alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl issubstituted with 0-6 independent occurrences of halogen, —OH, or C₁-C₆alkoxy; and each of m, n, and p is independently 0, 1, 2, 3, 4, or 5.

In some embodiments, ring C is aryl (e.g., phenyl). In some embodiments,ring D is heteroaryl (e.g., 1,2,4-oxadiazole). In some embodiments, R¹⁵is fluoro and n is 1. In some embodiments, p is 0. In some embodiments,m is 1. In some embodiments, R¹⁴ is —S(O)₂R^(G) and R^(G) ischlorophenyl. In some embodiments, R^(13a) is —CH₂CH₂CF₃ and R^(13b) ishydrogen. In some embodiments, each R¹¹ and R¹² is independentlyhydrogen.

In a further embodiment, the GSI is a compound described in U.S. Pat.No. 8,084,477. In one embodiment, the GSI is BMS-708163, i.e.,avagacestat, or(R)-2-((4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenyl)sulfonamido)-5,5,5-trifluoropentanamide,or a pharmaceutically acceptable salt thereof. In one embodiment, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (IV) or apharmaceutically acceptable salt thereof:

where R¹⁷ is selected from

R¹⁸ is lower alkyl, lower alkinyl, —(CH₂)_(n)-O-lower alkyl,—(CH₂)_(n)—S-lower alkyl, —(CH₂) _(n)—CN, —(CR′R″)_(n)—CF₃,—(CR′R″)_(n)—CH₂F, —(CR′R″) n-CH₂F, —(CH₂)_(n), —C(O)O-lower alkyl,—(CH₂)_(n)-halogen, or is —(CH₂)_(n)-cycloalkyl optionally substitutedby one or more substituents selected from the group consisting ofphenyl, halogen and CF₃; R′,R″ are each independently hydrogen, loweralkyl, lower alkoxy, halogen or hydroxy; R¹⁹, R²⁰ are each independentlyhydrogen, lower alkyl, lower alkoxy, phenyl or halogen; R²¹ is hydrogen,lower alkyl, —(CH₂)_(n)-CF₃ or —(CH2)_(n)-cycloalkyl; R²² is hydrogen orhalogen; R²³ is hydrogen or lower alkyl; R²⁴ is hydrogen, lower alkyl,lower alkinyl, —(CH₂)_(n)—CF₃, —(CH₂)_(n)-cycloalkyl or—(CH₂)_(n)-phenyl optionally substituted by halogen; R²⁵ is hydrogen,lower alkyl, —C(O)H, —O(O)-lower alkyl, —C(O)-CF₃, —C(O)-CH₂F,—C(O)-CHF2, —C(O)-cycloalkyl, —C(O)—(CH₂)_(n) -O-lower alkyl,—C(O)0—(CH₂)_(n)—cycloalkyl, —C(O)-phenyl optionally substituted by oneor more substituents selected from the group consisting of halogen and—C(O)O-lower alkyl, or is —S(O)2-lower alkyl, —S(O)₂—CF₃,—(CH₂)_(n)-cycloalkyl or is —(CH₂)_(n)-phenyl optionally substituted byhalogen; n is 0, 1, 2, 3 or 4.

In some embodiments, R¹⁷ is 5,7-dihydro-6H-dibenzo[b,d]azepin-6-onyl. Insome embodiments, each R¹⁹ and R²⁰ is independently —CH₃. In someembodiments, R¹⁸ is CH₂CF2CF₃.

In some embodiments, the GSI is a compound described in U.S. Pat. No.7,160,875. In one embodiment, the GSI is RO4929097, i.e.,(S)-2,2-dimethyl-N1-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N3-(2,2,3,3,3-pentafluoropropyl)malonamide,or a pharmaceutically acceptable salt thereof. In one embodiment, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of Formula (V) or apharmaceutically acceptable salt thereof:

where

q is 0 or 1; Z represents halogen, —CN, —NO₂, —N₃, —CF₃, —OR^(2a),—N(R^(2a))₂, —CO₂R^(2a), —OR^(2a), —COR^(2a), —CON(R^(2a))₂,—OCON(R^(2a))², —CONR^(2a)(OR^(2a)), —CON(R^(2a))₂, —(R^(2a))N(R^(2a))₂,—ONHC(═NOH)R^(2a), heterocyclyl, phenyl or heteroaryl, the heterocyclyl,phenyl or heteroaryl bearing 0-3 substituents selected from halogen,—CN, —NO₂, —CF₃, —OR^(2a), —N(R^(2a))₂, —CO₂R^(2a), —COR^(2a),—CON(R^(2a))₂ and C₁₋₄ alkyl; R²⁷ represents H, C₁₋₄ alkyl, or OH; R²⁶represents H or C₁₋₄ alkyl; with the proviso that when m is 1, R²⁶ andR²⁷ do not both represent C₁₋₄ alkyl; Ar¹ represents C₆₋₁₀ aryl orheteroaryl, either of which bears 0-3 substituents independentlyselected from halogen, —CN, —NO₂, —CF₃, —OH, —OCF₃, C₁₋₄ alkoxy or C₁₋₄alkyl which optionally bears a substituent selected from halogen, CN,NO₂, CF₃, OH and C₁₋₄ alkoxy; Ar² represents C₆₋₁₀ aryl or heteroaryl,either of which bears 0-3 substituents independently selected fromhalogen, —CN, —NO₂, —CF₃, —OH, —OCF₃, C₁₋₄ alkoxy or C₁₋₄ alkyl whichoptionally bears a substituent selected from halogen, —CN, —NO₂, —CF₃,—OH and C₁₋₄ alkoxy; R^(2a) represents H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C3_6cycloalkyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, any of which optionally bearsa substituent selected from halogen, —CN, —NO₂, —CF₃, —OR^(2b),—CO₂R^(2b), —N(R^(2b))₂, —CON(R^(2b))₂, Ar and COAr; or R^(2a)represents Ar; or two R^(2a) groups together with a nitrogen atom towhich they are mutually attached can complete an N-heterocyclyl groupbearing 0-4 substituents independently selected from ═O, ═S, halogen,C₁₋₄ alkyl, —CN, —NO₂, —CF₃, —OH, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl,CO₂H, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, carbamoyl, Ar andCOAr; R^(2b) represents H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylC₁₋₆ alkyl, C₂₋₆ alkenyl, any of which optionally bears asubstituent selected from halogen, —CN, —NO₂, —CF₃, —OH, C₁₋₄ alkoxy,C₁₋₄ alkoxycarbonyl, —CO₂H, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino,carbamoyl, Ar and COAr; or R^(2b) represents Ar; or two R^(2b) groupstogether with a nitrogen atom to which they are mutually attached cancomplete an N-heterocyclyl group bearing 0-4 substituents independentlyselected from ═O, ═S, halogen, C₁₋₄ alkyl, —CN, —NO₂, CF₃ , —OH, C₁₋₄alkoxy, C₁₋₄ alkoxycarbonyl, —CO₂H, amino, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; Ar represents phenyl or heteroarylbearing 0-3 substituents selected from halogen, C₁₋₄ alkyl, —CN, —NO₂,—CF₃, —OH, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, amino, C₁₋₄ alkylamino,di(C₁₋₄ alkyl)amino, carbamoyl, C₁₋₄ alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl.

In some embodiments, q is 1. In some embodiments, Z is CO₂H. In someembodiments, each of R²⁷ and R²⁶ is independently hydrogen. In someembodiments, Ar¹ is chlorophenyl. In some embodiments, Ar² isdifluorophenyl.

In some embodiments, the GSI is a compound described in U.S. Pat. No.6,984,663. In one embodiment, the GSI is MK-0752, i.e.,3-((1S,4R)-4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoicacid, or a pharmaceutically acceptable salt thereof. In someembodiments, the GSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (VI) or apharmaceutically acceptable salt thereof.

where A′ is absent or selected from

and —S(O)2-;

Z is selected from —CH₂, —CH(OH), —CH(C₁-C₆ alkyl), —CH(C₁-C₆ alkoxy),—CH(NR³³R³⁴), —CH(CH₂(OH)), —CH(CH(C₁-C4 alkyl)(OH)) and —CH(C(C₁-C4alkyl)(C₁-C4 alkyl)(OH)), for example —CH(C(CH₃)(CH₃)(OH)) or—CH(C(CH₃)(CH₂CH₃)(OH)); R²⁷ is selected from C₁-C₂₀ alkyl, C₂-C₂₀alkenyl, C₂-C₂₀ alalkynyl, C₁-C₂₀ alkoxy, C₂-C₂₀ alalkenoxy, C₁-C₂₀hydroxyalkyl, C₃-C₈ cycloalkyl, benzo(C₃-C₈ cycloalkyl), benzo(C₃-C₈heterocycloalkyl), C₄-C₈ cycloalkenyl, (C₅-C₁₁)bi- or tricycloalkyl,benzo(C₅-C₁₁)bi- or tricycloalkyl, C₇-C₁₁ tricycloalkenyl, (3-8membered) heterocycloalkyl, C₆-C₁₄ aryl and (5-14 membered) heteroaryl,where each hydrogen atom of the alkyl, alkenyl, alkynyl, alkoxy andalkenoxy is optionally independently replaced with halo, and where thecycloalkyl, benzo(C₃-C₈ cycloalkyl), cycloalkenyl, (3-8 membered)heterocycloalkyl, C₆-C₁₄ aryl and (5-14 membered) heteroaryl isoptionally independently substituted with from one to four substituentsindependently selected from C₁-C₁₀ alkyl optionally substituted withfrom one to three halo atoms, C₁-C₁₀ alkoxy optionally substituted withfrom one to three halo atoms, C₁-C₁₀ hydroxyalkyl, halo, e.g., fluorine,—OH, —CN, —NR³³R³⁴, —C(═O)NR³³R³⁴, —C(═O)R³⁵, C₃-C₈ cycloalkyl and (3-8membered) heterocycloalkyl; R²⁸ is selected from hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₃-C₈ cycloalkyl and C₅-C₈ cycloalkenyl, where R²⁸ isoptionally independently substituted with from one to three substituentsindependently selected from C₁-C₄ alkyl optionally substituted with fromone to three halo atoms, C₁-C₄ alkoxy optionally substituted with fromone to three halo atoms, halo and —OH; or R²⁷ and R²⁸ together with theA′ group when present and the nitrogen atom to which R²⁸ is attached, orR²⁷ and R²⁸ together with the nitrogen atom to which R²⁷ and R²⁸areattached when A′ is absent, can optionally form a four to eight memberedring; R²⁹ is selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl and (3-8 membered)heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and heterocycloalkyl are each optionally independentlysubstituted with from one to three substituents independently selectedfrom C₁-C₄alkoxy, halo, —OH—S(C₁-C₄)alkyl and (3-8 membered)heterocycloalkyl; R³⁰ is hydrogen, C₁-C₆ alkyl or halo; or R²⁹ and R³⁰can together with the carbon atom to which they are attached optionallyform a moiety selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, morpholino, piperidino, pyrrolidino, tetrahydrofuranyl andperhydro-2H-pyran, where the moiety formed by R²⁹ and R³⁰ is optionallysubstituted with from one to three substituents independently selectedfrom C₁-C₆ alkyl optionally substituted with from one to three haloatoms, C₁-C₆ alkoxy optionally substituted with from one to three haloatoms, halo, —OH, —CN and allyl; R³¹ is selected from hydrogen, C₁-C₆alkyl, C₂-C₆ alkylene, C₁-C₆ alkoxy, halo, —CN, C₃-C₁₂ cycloalkyl,C₄-C₁₂ cycloalkenyl and C₆-C₁₀ aryl, (5-10 membered) heteroaryl, wherethe alkyl, alkylene and alkoxy of R³¹are each optionally independentlysubstituted with from one to three substituents independently selectedfrom halo and —CN, and where the cycloalkyl, cycloalkenyl and aryl andheteroaryl of R³¹are each optionally independently substituted with fromone to three substituents independently selected from C₁-C₄ alkyloptionally substituted with from one to three halo atoms, C₁-C₄ alkoxyoptionally substituted with from one to three halo atoms, halo and —CN;R³² is selected from hydrogen, C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, C₁-C₂₀hydroxyalkyl, C₃-C₁₂ cycloalkyl, C₄-C₁₂ cycloalkenyl, (C₅-C₂₀) bi- ortricycloalkyl, (C₇-C₂₀)bi- or tricycloalkenyl, (3-12 membered)heterocycloalkyl, (7-20 membered) hetero bi- or heterotricycloalkyl,C₆-C₁₄ aryl and (5-15 membered) heteroaryl, where R³² is optionallyindependently substituted with from one to four substituentsindependently selected from C₁-C₂₀ alkyl optionally substituted withfrom one to three halo atoms, C₁-C₂₀ alkoxy, —OH, —CN, —NO₂, —NR³³R³⁴,—C(═O)NR³³R³⁴, —C(═O)R³⁵, —C(═O)OR³⁵, —S(O)_(n)NR³³R³⁴, —S(O)_(n)R³⁵,C₃-C₁₂ cycloalkyl, (4-12 membered) heterocycloalkyl optionallysubstituted with from one to three OH or halo groups, (4-12 membered)heterocycloalkoxy, C₆-C₁₄ aryl, (5-15 membered) heteroaryl, C₆-C₁₂aryloxy and (5-12 membered) heteroaryloxy; or R³³ and R³⁴ can togetherwith the carbon and nitrogen atoms to which they are respectivelyattached optionally form a (5-8 membered) heterocycloalkyl ring, a (5-8membered) heterocycloalkenyl ring or a (6-10 membered) heteroaryl ring,where the heterocycloalkyl, heterocycloalkenyl and heteroaryl rings areeach optionally independently substituted with from one to threesubstituents independently selected from halo, C₁-C₆ alkyl, optionallysubstituted with from one to three halo atoms, C₁-C₆ alkoxy optionallysubstituted with from one to three halo atoms, C₁-C₆ hydroxyalkyl, —OH,—(CH₂)_(zero-10)NR³³R³⁴, —(CH₂)zero-10C(═O)NR³³R³⁴, —S(O)₂NR³³R³⁴ andC₃-C₁₂ cycloalkyl; R³³ and R³⁴ are each independently selected fromhydrogen, C₁-C₁₀ alkyl where each hydrogen atom of the C₁-C₁₀ alkyl isoptionally independently replaced with a halo atom, e.g., a fluorineatom, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₆ alkoxy where each hydrogenatom of the C₁-C₆ alkoxy is optionally independently replaced with ahalo atom, C₂-C₆ alkenoxy, C₂-C₆ alkynoxy, —C(═O)R11, —S(O)_(n)R11,C₃-C₈ cycloalkyl, C₄-C₈ cycloalkenyl, (C₅-C₁₁)bi- or tricycloalkyl,(C₇-C₁₁)bi- or tricycloalkenyl, (3-8 membered) heterocycloalkyl, C₆-C₁₄aryl and (5-14 membered) heteroaryl, where the alkyl and alkoxy are eachoptionally independently substituted with from one to three substituentsindependently selected from halo and —OH, and where the cycloalkyl,cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,heterocycloalkyl, aryl and heteroaryl are each optionally independentlysubstituted with from one to three substituents independently selectedfrom halo, —OH, C₁-C₆ alkyl optionally independently substituted withfrom one to six halo atoms, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₂-C₆ alkenoxy, C₂-C₆ alkynoxy and C₁-C₆ hydroxyalkyl; or NR³³R³⁴ canform a (4-7 membered) heterocycloalkyl, where the heterocycloalkyloptionally comprises from one to two further heteroatoms independentlyselected from N, O, and S, and where the heterocycloalkyl optionallycontains from one to three double bonds, and where the heterocycloalkylis optionally independently substituted with from one to threesubstituents independently selected from C₁-C₆ alkyl optionallysubstituted with from one to six halo atoms, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₂-C₆ alkenoxy, C₂-C₆ alkynoxy, C₁-C₆hydroxyalkyl, C₂-C₆hydroxyalkenyl, C₂-C₆hydroxyalkynyl, halo, —OH, —CN,—NO₂, —C(═O)R³⁵, —C(═O)OR³⁵, —S(O)_(n)R³⁵ and —S(O)_(n)NR³³R³⁴; R³⁵ isselected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₄-C₈cycloalkenyl, (C₅-C₁₁)bi- or tricycloalkyl, —(C₇-C₁₁)bi- ortricycloalkenyl, (3-8 membered) heterocycloalkyl, C₆-C₁₀ aryl and (5-14membered) heteroaryl, where the alkyl of R³⁵ is optionally independentlysubstituted with from one to three substituents independently selectedfrom —OH, —CN and C₃-C₈ cycloalkyl, and where each hydrogen atom of thealkyl is optionally independently replaced with a halo atom, e.g., afluorine atom, and where the cylcoalkyl, cycloalkenyl, heterocycloalkyl,aryl and hetereoaryl of R³⁵ are each optionally independentlysubstituted with from one to three substituents independently selectedfrom halo, C₁-C₈ alkyl optionally substituted with from one to threehalo atoms, —OH, —CN and C₃-C₈cycloalkyl; n is in each instance aninteger independently selected from zero, 1, 2 and 3; and thepharmaceutically acceptable salts of such compounds.

In some embodiments, the GSI is a compound described in U.S. Pat. No.7,795,447. In one embodiment, the GSI is PF-3084014, i.e., nirogacestator(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, or a pharmaceutically acceptable saltthereof.

In some embodiments, the GSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of formula (VII):

or a pharmaceutically acceptable salt thereof where k is 1, 2, or 3; R³⁶is aryl C₁-C₈ alkyl, aryl C₂-C₆ alkenyl, or arylalkynyl, where the arylgroup is substituted with 0-5 occurrences of C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, haloalkyl, haloalkoxy, heteroaryl, heteroaryl(C₁-C₆)alkoxy,arylalkoxy, aryloxy, C₁-C₆ alkoxycarbonyl, —OCH₂CH₂O—, —OCH₂O—,—C(O)NR⁴³R⁴⁴, —NHR′, —NR′R″, —N(R¹⁶)C(O)R¹⁷, heterocycloalkyl, phenyl,aryl C₁-C₆ alkanoyl, phenylalkoxy, phenyloxy, CN, —SO₂-aryl,—S(O)_(n)R²⁵, —(C₁-C₄ alkyl)-S(O)_(x)R²⁵, —(C₁-C₄ alkyl)—SO₂-aryl, OH,C₁-C₆ thioalkoxy, C₂-C₆ alkenyl, —OSO₂-aryl, or CO₂H, where eachheteroaryl is independently substituted with 0-3 occurrences of C₁-C₆alkyl, heteroaryl substituted with 0-2 occurrences of halogen, alkyl,alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl or CN, C₁-C₆ alkoxy, C₁-C₄alkoxy C₁-C₄ alkyl, C₃-C₆ cycloalkyl, halogen, or phenyl substitutedwith 0-5 occurrences of halogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃,OCF₃, CN, or C₁-C6 thioalkoxy,where each heterocycloalkyl and aryl are independently substituted with0-2 occurrences of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy,alkoxyalkyl or CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,C₃-C₆ cycloalkyl, halogen, or phenyl substituted with 0-5 occurrences ofhalogen, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, CN, or C₁-C₆thioalkoxy; R¹⁶ is hydrogen or C₁-C₆ alkyl; R¹⁷ is C₁-C₆ alkyl, aryl,heteroaryl, C₁-C₆ alkoxy, OH, aryloxy, heteroaryloxy, aryl(C₁-C₆)alkoxy,—NR¹⁸R¹⁹, cycloalkyl, or arylalkyl, where the cyclic portions of eachare independently substituted with 0-5 occurrences of alkyl, alkoxy,halo, haloalkyl, haloalkoxy, CN, NH₂, NH(alkyl), N(alkyl) (alkyl), CO₂H,or C₁-C₆ alkoxycarbonyl; R¹⁸ and R¹⁹ are independently hydrogen, C₁-C₆alkyl, aryl, heteroaryl, heterocycloalkyl or aryl(C₁-C₆ )alkyl, wherethe cyclic portions of each are substituted with 0-3 occurrences ofalkyl, alkoxy, halogen, hydroxyl, CF₃, or OCF₃; each R′ is independentlyhydrogen, C₁-C₆ alkyl, aryl, aryl(C₁-C₄)alkyl, C₁-C₆ alkanoyl, C₃-C₈cycloalkyl, aryl(C₁-C₆)alkanoyl, heterocycloalkyl,heteroaryl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl,heterocycloalkyl(C₁-C₆)alkanoyl, or heteroaryl(C₁-C₆)alkanoyl, where thealkyl portion of the alkyl and alkanoyl groups are optionallysubstituted with halogen or C₁-C₆ alkoxy and the aryl and heteroarylgroups are optionally substituted with alkyl, alkoxy, halogen,haloalkyl, haloalkoxy; each R″ is independently hydrogen or C₁-C₆ alkyl,where the alkyl group is optionally substituted with halogen;

R³⁶ is C₃-C₇ cycloalkyl(C₁-C₆ alkyl) where the cyclic portion issubstituted with 0-5 occurrences of halogen, C₁-C₆ alkyl, OH,alkoxycarbonyl, or C₁-C₆ alkoxy; or R³⁶ is C₁-C₁₄ alkyl, C₂-C₁₆ alkenyl,or C₂-C₈ alkynyl, each of which is substituted 0-5 occurrences of OH,halogen, C₁-C₆ alkoxy, aryl, arylalkoxy, aryloxy, heteroaryl,heterocycloalkyl, aryl(C₁-C₆)alkyl, —CO₂(C₁-C₆ alkyl), —NR′R″, C₁-C₆thioalkoxy, —NHS(O)_(x)R²⁵, —N(C₁-C₆ alkyl)-S(O)_(n)R²⁵, —S(O)_(n)R²⁵,—C(O)NR⁴³R⁴⁴, —N(R¹⁶)C(O)NR¹⁶R¹⁷, or —N(R₁₆)C(O)R¹⁷; where the abovearyl groups are substituted with 0-3 occurrences of OH, C₁-C₆ alkoxy,C₁-C₆ alkyl, or halogen; R⁴³ and R⁴⁴ are independently hydrogen, C₁-C₆alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkanoyl, alkenyl, cycloalkyl, alkynyl,cycloalkenyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl,where each alkyl is substituted with 0-3 occurrences of NH₂, NH(C₁-C₆alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), OH, C₁-C₆ thioalkoxy,heterocycloalkyl, aryl, heteroaryl, CN, halogen, or alkoxy optionallysubstituted with OH or phenyl, where the aryl, heteroaryl andheterocycloalkyl groups are substituted with 0-3 occurrences of C₁-C₄alkyl, C1-C₄ alkoxy, CF₃, OCF₃, OH, halogen, thioalkoxy, phenyl orheteroaryl; or R⁴³, R⁴⁴, and the nitrogen to which they are attachedform a heterocycloalkyl ring containing from 3 to 7 ring members, wherethe cyclic portions of R⁴³ and R⁴⁴ or the heterocyclic ring formed fromR⁴³, R⁴⁴, and the nitrogen to which they are attached are substitutedwith 0-3 occurrences of alkyl, alkoxy, halo, OH, thioalkoxy, NH₂,NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl), CF₃, OCF₃, phenyloptionally substituted with a halogen, —(C₁-C₄ alkyl)-N(H or C₁-C₄alkyl)-phenyl, C₁-C₄ hydroxyalkyl, arylalkoxy, arylalkyl, arylalkanoyl,C(O)N H₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl),heterocycloalkylalkyl, C₁-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl, heteroaryl,or —SO₂(C₁-C₆ alkyl); x is 0, 1, or 2; R²⁵ is C₁-C₆ alkyl, OH, NR²⁶R²⁷;R²⁶ and R²⁷ are independently hydrogen, C₁-C₆ alkyl, phenyl(C₁-C₄alkyl), aryl, or heteroaryl; or R²⁶, R²⁷ and the nitrogen to which theyare attached form a heterocycloalkyl ring; R³⁶ is heteroaryl(C₁-C₆)alkylwhere the cyclic portion is substituted 0-5 occurrences of halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, aryl,arylalkyl, aryloxy, heteroaryl, —SC₂-aryl, —S(O)_(x)R₂₅, (C₁-C₄alkyl)-S(O)_(x)R₂₅, CN, C₁-C₆ thioalkoxy, C₁-C₆ alkoxycarbonyl, —NR′R″,—C(O)NR′R″, heterocycloalkyl, where the above aryl groups aresubstituted with 0-4 occurrences of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or CN; where the above heteroaryl andheterocycloalkyl groups are substituted with 0-3 occurrences of halogen,CF₃, (C₁-C₄)alkyl, C₁-C₆ thioalkoxy, OH, C₁-C₄ hydroxyalkyl, or C₁-C₄alkoxy; or

R³⁶ is heterocycloalkyl(C₁-C₆ alkyl) where the cyclic portion issubstituted with 0-3 occurrences of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, aryl, arylalkyl, aryloxy, heteroaryl,—SO₂-aryl, —S(O)_(x)R²⁵, (C₁-C₄ alkyl)-S(O)_(x)R²⁵, CN, C₁-C₆thioalkoxy, C₁-C₆ al koxycarbonyl, —NR′R″, —C(O)NR′R″, heterocycloalkyl;

R³⁷ is hydrogen, C₁-C₆ alkyl, or phenyl(C₁-C4)alkyl; R³⁸ is hydrogen,halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, CN; R³⁹ ishydrogen, halogen, C₁-C₆ alkyl optionally substituted with —CO₂—(C₁-C₆alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, CN, aryloxy,isocyanato, —SO₂(C₁-C₆ alkyl), —NHR′, —NR′R″, C₁-C₆ alkanoyl,heteroaryl, aryl; or

R³⁸ and R³⁹ and the carbons to which they are attached form aheterocycloalkyl ring which is substituted with 0-3 occurrences of C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, or C₁-C₄ alkanoyl where the alkanoyl groupis substituted with 0-3 halogen atoms; R⁴⁰ is hydrogen, —SO₂NR′R″,halogen; or R³⁹ and R⁴° and the carbons to which they are attached forma benzo ring; or R³⁹ and R⁴⁰ and the carbons to which they are attachedform a 1-oxa-2,3-diazacyclopentyl ring;

R⁴° and R⁴¹ are independently hydrogen or F; or R⁴¹, R⁴¹, and thecarbons to which they are attached for a 1,2,5-oxadiazolyl ring; or R⁴⁰, R⁴¹, and the carbons to which they are attached form a naphthyl ring.

In some embodiments, R³⁶ is 4-bromobenzyl. In some embodiments, R³⁷ ishydrogen. In some embodiments, k is 2. In some embodiments, each of R³⁸,R⁴⁰, R⁴¹, and R⁴² is independently hydrogen. In some embodiments, R³⁹ ischloro.

In some embodiments, the GSI is a compound described in U.S. Pat. No.7,939,657. In one embodiment, the GSI is ELN-318463, i.e., HY-50882 or(R)-N-(4-bromobenzyl)-4-chloro-N-(2-oxoazepan-3-yl)benzenesulfonamide,or a pharmaceutically acceptable salt thereof. In some embodiments, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (VIII):

or a pharmaceutically acceptable salt thereof, where R₁ is —CH₂CF₃ or—CH₂CH₂CF₃; R₂ is —CH₂CF₃, —CH₂CH₂CF₃, or —CH₂CH₂CH₂CF₃; R₃ is hydrogenor —CH₃; each R_(a) is independently F, CI, —CN, —OCH₃, and/or—NHCH₂CH₂OCH₃; and z is 0, 1, or 2.

In some embodiments, R¹ is —CH₂CH₂CF₃CH₂CH₂CF₃. In some embodiments,R₂—CH₂CH₂CF₃. In some embodiments, R₃ is —CH₃. In some embodiments, z is0.

In some embodiments, the GSI is a compound described in U.S. Pat. No.8,629,136. In one embodiment, the GSI is BMS-906024, i.e.,(2R,3S)-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinamide,or a pharmaceutically acceptable salt thereof. In one embodiment, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound described in U.S. Pat. No.8,629,136. In one embodiment, the GSI is LY3039478, crenigacestat or4,4,4-trifluoro-N-((R)-1-(((S)-5-(2-hydroxyethyl)-6-oxo-6,7-dihydro-5H-benzo[d]pyrido[2,3-b]azepin-7-yl)amino)-1-oxopropan-2-yl)butanamide,or a pharmaceutically acceptable salt thereof. In some embodiments, theGSI is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is BMS-299897, i.e.,2-[(1R)-1-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)amino]ethyl-5-fluorobenzenebutanoicacid or a pharmaceutically acceptable salt thereof. In some embodiments,the GSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is LY-411575, i.e., LSN-411575,(S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)propanamide,or a pharmaceutically acceptable salt thereof. In some embodiments, theGSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is DAPT,N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethylester or a pharmaceutically acceptable salt thereof. In someembodiments, the GSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of the following formulae:

where, z1 is 0, 1 or 2; X¹ is C(R³) or N; R¹ is hydrogen, halogen, —N₃,—CF₃, —CCI₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(1A), —NR^(1A)R^(1B),—COOR^(1A), —C(O)NR^(1A)R^(1B), —NO₂, —SR¹A, —S(O)_(n1)OR^(1A),—S(O)_(n1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B), —ONR^(1A)R^(1B),—NHC(O)NHNR^(1A)R^(1B), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —N₃, —CF₃, —CCI₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(2A),—NR^(2A)R^(2B), —COOR^(2A), —C(O)NR^(2A)R^(2B), —NO₂, —SR^(2A),—S(O)_(n2)R^(2A), —S(O)_(n2)OR^(2A), —S(O)_(n2)NR^(2A)R^(2B),—NHNR^(2A)R^(2B), —ONR^(2A)R^(2B), —NHC(O)NHNR^(2A)R^(2B), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —N₃, —CF₃, —CCI₃,—CBr₃, —CCI₃, —CN, —CHO, —OR^(3A), —NR^(3A)R^(3B), —COOR^(3A),—C(O)NR^(3A)R^(3B), —NO₂, —SR^(3A), —S(O)_(n3)R^(3A), —S(O)_(n3)OR^(3A),—S(O)_(n3)ONR^(3A)R^(3B), —NHNR^(3A)R^(3B), —ONR^(3A)R^(3B),—NHC(O)NHNR^(3A)R^(3B), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —N₃, —CF₃, —CCI₃, —CBr₃, —CCI₃, —CN, —CHO, —OR″,—NR^(4A)R^(4B), —COOR^(4A), —O(O)NR^(4A)R^(4B), 13 NO₂, —SR″ ,—S(O)_(n4)R^(4A), —S(O)_(n4)OR^(4A), —S(O)_(n4)NR^(4A)R^(4B),—NHNR^(4A)R^(4B), —ONR^(4A)R^(4B), —NHC(O)NHNR^(4A)R^(4B), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCI₃,—CBr₃, —CCI₃, —CN, —CHO, —OR^(5A), —NR^(5A)R^(5B), —COOR^(5A),—C(O)NR^(5A)R^(5B), —NO₂, —SR^(5A), —S(O)_(n5)R^(5A), —S(O)_(n5)OR^(5A),—S(O)_(n5)NR^(5A)R^(5B), —NHNR^(5A)R^(5B), —ONR^(5A)R^(5B),—NHC(O)NHNR^(5A)R^(5B), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, where R⁴and R⁵ are optionally joined together to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl; R⁶ is —CF₃, substituted or unsubstituted cyclopropyl, orsubstituted or unsubstituted cyclobutyl; R⁷ is independently hydrogen,halogen, —N₃, —CF₃, —CCI₃, —CBr₃, —CCI₃, —CN, —CHO, —OR^(7A),—NR^(7A)R^(7B), —COOR^(7A), —C(O)NR^(7A)R^(7B), —NO₂, —SR^(7A),—S(O)_(n7)R^(7A), —S(O)_(n7)OR^(7A), —S(O)_(n7)NR^(7A)R^(7B),—NHNR^(7A)R^(7B), —ONR^(7A)R^(7B), —NHC(O)NHNR^(7A)R^(7B), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B),R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), R^(4B), R^(5A), R^(5B), R^(7A), —R^(7B)are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; and n1,n2, n3, n4, n5 and n7 are independently 1 or 2.

In some embodiments, the GSI of formulae (VIII-a), (VIII-b), (VIII-c),or (VIII-d) is described in International Patent Publication No. WO2014/165263 (e.g., in embodiments P1-P12). In some embodiments, the GSIof formulae (VIII-a), (VIII-b), (VIII-c), or (VIII-d) is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (IX):

or a pharmaceutically acceptable salt thereof, where A is a 4 to 7membered spirocyclic ring comprising at least one heteroatom selectedfrom the group consisting of N, O, S, S(O)₂, P(O)R¹, and N—S(O)₂—R¹,where the spirocyclic ring is optionally substituted with 1 to 3substituents selected from the group consisting of C1-3alkyl and ═O; R¹is C1-6alkyl optionally substituted with halo; each Lis independentlyselected from the group consisting of 1) C1-3alkyl optionallysubstituted with halo, and 2) halo; each L² is independently selectedfrom the group consisting of 1) C1-3alkyl optionally substituted withhalo, and 2) halo; and n is 0 to 3.

In some embodiments, the GSI is a compound described in U.S. PatentPublication No. US-2015-307533 (e.g., in the Table on pages 13-16). Insome embodiments, the GSI is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (X):

or a pharmaceutically acceptable salt thereof, where R¹ is hydroxy orfluoro; R² is C₁-C₄ alkyl; R³ is hydrogen or phenyl; R⁴ is hydrogen,phenyl, or C₁-C₄ alkyl; R⁵ is hydrogen or phenyl; provided that one ofR³, R⁴, and R⁵ is other than hydrogen and the other two are hydrogen.

In some embodiments, the GSI is a compound described in U.S. Pat. No.8,188,069. In one embodiment, the GSI is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (XI):

or a pharmaceutically acceptable salt thereof, where: R¹ is 1) hydrogen,2) (C1-C6)alkyl optionally substituted with 1 to 5 halogens or phenyl,where the phenyl is optionally substituted with 1 to 3 halogens, 3)phenyl optionally substituted with 1 to 3 (C1-C6)alkyls or 1 to 5halogens, or 4) (C4-C6)cycloalkyl optionally substituted with 1 to 3(C1-C6)alkyls or 1 to 5 halogens; R² is 1) hydrogen, 2) (C1-C6)alkyloptionally substituted with 1 to 5 halogens or phenyl, where the phenylis optionally substituted with 1 to 3 halogens, or 3) phenyl optionallysubstituted with 1 to 3 halogens; R³ is (C1-C6)alkyl, —OH or halogen;

X is —NR⁴—, 13 O—, —S—, or —SO₂—; R⁴ is hydrogen or (C1-C3)alkyl;

p is 1 to 3; m is 0 or 1; n is 0 to 3; and Ar²—Ar¹ is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound described in U.S. Pat. No.9,096,582 (e.g., in the Table on pages 13-17). In some embodiments, theGSI is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the GSI is a compound of formula (XII):

or a pharmaceutically acceptable salt thereof, where or thepharmaceutically acceptable salts thereof, where: R¹, R², R³, R⁸, R⁹,R¹⁰, and W are independently selected; W is selected from the groupconsisting of; —S(O)—, and —S(O)₂—; R¹ is selected from the groupconsisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, fusedbenzocycloalkyl (i.e., benzofusedcycloalkyl), fusedbenzoheterocycloalkyl (i.e., benzofusedheterocycloalkyl), fusedheteroarylcycloalkyl (i.e., heteroarylfusedcycloalkyl), fusedheteroarylheterocycloalkyl (i.e., heteroarylfused-heterocycloalkyl),heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl, —andheterocyclyalkyl-; where each of the alkyl-, alkenyl- and alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl-,cycloalkylalkyl-, fused benzocycloalkyl, fused benzoheterocycloalkyl,fused heteroarylcycloalkyl, fused heteroarylheterocycloalkyl,heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl andheterocyclyalkyl-R¹ groups is optionally substituted with 1-5independently selected R²¹ groups; R² and R³ are each independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-,heterocyclenyl-, and heterocyclyalkyl-; where each of the alkyl-,alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkenyl, cycloalkylalkyl-, cycloalkenyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl-, heterocyclenyl- and heterocyclyalkyl-R¹ groups is optionally substituted with 1-5 independently selected R²¹groups; or R² and R³ taken together, along with the atoms to which theyare bound, form a ring selected from the group consisting of: (a) a 5 to6 membered heterocycloalkyl ring, the heterocycloalkyl ring optionallycomprising, in addition to W and in addition to the N adjacent to W, atleast one other heteroatom independently selected from the groupconsisting of: —O—, —S(O)—, —S(O)₂, and —C(O)—, and (b) a 5 to 6membered heterocycloalkenyl ring, the heterocycloalkenyl ring optionallycomprising, in addition to W and in addition to the N adjacent to W, atleast one other heteroatom independently selected from the groupconsisting of: —O—, —S(O)—, —S(O)₂, and —C(O)—; where the ring isoptionally substituted with 1-5 independently selected R²¹ groups; or R²and R³ taken together along with the atoms to which they are bound, andR¹ and R³ are taken together along with the atoms to which they arebound, form the fused ring moiety:

where Ring A is a ring selected from the group consisting of:

(a) a 5 to 6 membered heterocycloalkyl ring, the heterocycloalkyl ringoptionally comprising, in addition to W and in addition to the Nadjacent to W, at least one other heteroatom independently selected fromthe group consisting of: —O—, —NR¹⁴—, —S(O)—, —S(O)₂, and —C(O)—, and(b) a 5 to 6 membered heterocycloalkenyl ring, the heterocycloalkenylring optionally comprising, in addition to W and in addition to the Nadjacent to W, at least one other heteroatom independently selected fromthe group consisting of: —O—, —NR¹⁴—, —S(O)—, —S(O)₂, and —C(O)—, andwhere the fused ring moiety is optionally substituted with 1-5independently selected R²¹ groups; or R¹ and R³ taken together with theatoms to which they are bound form a fused benzoheterocycloalkyl ring,and where the fused ring is optionally substituted with 1-5independently selected R²¹ groups, R⁸ is selected from the groupconsisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl-, heterocyclenyl- and heterocyclyalkyl-;where each of the R⁸ alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl, heterocyclenyl- and heterocyclyalkyl- isoptionally substituted with 1-3 independently selected R²¹ groups; R⁹ isselected from the group consisting of: alkyl-, alkenyl-, alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl,cycloalkylalkyl, heteroaryl-, heteroarylalkyl-, heterocyclyl-,heterocyclenyl-, and heterocyclyalkyl-, where each of the R⁹ alkyl-,alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkenyl, cycloalkyl alkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl-, heterocyclenyl-, heterocyclyalkyl- and heterocyclyalkyl-is optionally substituted with 1-3 independently selected R²¹ groups;

R¹⁰ is selected from the group consisting of: a bond, alkyl-, alkenyl-,alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-,heterocyclenyl-, heterocyclyalkyl-, heterocyclyalkenyl-,

where X is selected from the group consisting of: O, —N(R¹⁴)— or —S—;and where each of the R¹⁰ moieties is optionally substituted with 1-3independently selected R²¹ groups; R¹⁴ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, heterocyclylalkyl,heterocyclyalkenyl-, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —ON,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶); R¹⁵, R¹⁶ andR¹⁷ are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, arylheterocyclyl, (R¹⁸)_(n)-alkyl, (R¹⁸)_(n)-cycloalkyl,(R¹⁸)_(n)-cycloalkylalkyl, (R¹⁸)_(n)-heterocyclyl,(R¹⁸)_(n)-heterocyclylalkyl, (R¹⁸)_(n)-aryl, (R¹⁸)_(n)-arylalkyl,(R¹⁸)_(n)-heteroaryl and (R¹⁸)_(n)-heteroarylalkyl; each R¹⁸ isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂, halo,heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹, —C(O)OH,—C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)2R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl,—O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); or two R¹⁸ moieties on adjacent carbonscan be linked together to form a

R¹⁹ is selected from the group consisting of: alkyl, cycloalkyl, aryl,arylalkyl and heteroarylalkyl; R²⁰ is selected from the group consistingof: alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl and heteroarylalkyl; each R²¹ is independently selected fromthe group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —ON, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁶)(R¹⁶),—CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁶)(R¹⁶), —C(═NOR¹⁶)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), —alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —OH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; where each of the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl R²¹ groups is optionally substituted with 1 to 5independently selected R²² groups; and each R²² group is independentlyselected from the group consisting of alkyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, —alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),—alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷); —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.

In some embodiments, the GSI is a compound described in U.S. PatentPublication No. US-2011-0257163 (e.g., in paragraphs [0506] to [0553]).In some embodiments, the compound of formula (XII) is a pharmaceuticallyacceptable ester. In some embodiments, the compound of formula (XII) isselected from:

and pharmaceutically acceptable salts thereof.

In some embodiments, the GSI is a compound of formula (XIII):

or a pharmaceutically acceptable salt thereof, where the A-ring is aryl,cycloalkyl, heteroaryl or heterocycloalkyl, where each ring isoptionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, haloalkyl,haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy, —S(O)₀₋₂—(C₁-C₆ alkyl),—NR₁₀R₁₁, C₁-C₆ alkanoyl, C₀-C₃alkylCO₂R′, heteroaryl, heterocycloalkyl,aryl, aralkyl, or —SO₂NR₁₀R₁₁; R₁ and R₂ combine to form a [3.3.1] or a[3.2.1] ring system, where 0 or 1 of the carbons in the ring system isoptionally replaced with an —O—, —S(O)_(x)—, or —NR₁₅—group; and wherethe [3.3.1] or [3.2.1] ring system is optionally substituted with 1, 2,3, or 4 groups that are independently oxo, halogen, C₁-C₆ alkyl,—O(C₁-C₂ alkyl)O—, —S(C₁-C₂ alkyl)S—, C₂-C₆ alkenyl, C₁-C₆ haloalkyl,C₂-C₆ alkynyl, hydroxy, hydroxyalkyl, C₁-C₆ alkoxy, haloalkoxy,—C(O)OR—, —(C₁-C₄alkyl)—C(O)OR₁₆, —CONR₁₀R₁₁, —OC(O)NR₁₀R″, —NR′C(O)OR″,—NR′S(O)₂R″, —OS(O)₂R′, —NR′COR″, CN, ═N—NR₁₂, or ═N—O—R₁₃; where x is0, 1, or 2; R₁₀ and R₁₁ at each occurrence are independently hydrogen orC₁-C₆ alkyl, where the alkyl is optionally substituted with an aryl,where the aryl is optionally substituted with 1 to 5 groups that areindependently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy,CN or NO₂; or

R₁₀ and R₁₁ together can form a 3-8 membered ring optionally includingan additional heteroatom such as N, O or S; R₁₂ is hydrogen, C₁-C₆ alkylor —SO₂-aryl, where the aryl is optionally substituted with 1 to 5groups that are independently halogen, hydroxyl, alkyl, alkoxy,haloalkyl, haloalkoxy, CN or NO₂; R₁₃ is hydrogen or C₁-C₆ alkyloptionally substituted with aryl, hydroxyl, or halogen, where the arylis optionally substituted with 1 to 5 groups that are independentlyhalogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂;

R₁₅ is hydrogen, aryl, heteroaryl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with aryl, hydroxyl, or halogen, where thearyl groups are optionally substituted with 1 to 5 groups that areindependently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy,CN or NO₂; and R′ and R″ are independently hydrogen, C₁-C₆ alkyl,haloalkyl, C₂-C₆ alkenyl or phenyl optionally substituted with 1 to 5groups that are independently halogen, C₁-C₆ alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy, —SO₂—(C₁-C₆alkyl),—NR₁₀R₁₁, C₁-C₆ alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁.

In some embodiments, the GSI is a compound described in U.S. PatentPublication No. US-2011-178199 (e.g., in paragraphs [0798] to [0799] andTables 1-4). In some embodiments, the compound of formula (XIII)comprises a bridged n-bicyclic sulfonamide or a pharmaceuticallyacceptable salt thereof. In some embodiments, the GSI is selected from:

and pharmaceutically acceptable salts thereof.

In some embodiments, the GSI is a compound of formula (XIV):

or a pharmaceutically acceptable salt thereof, where R is selected fromthe group consisting of: (1) -pyridinyl, (2) -pyrazolinyl, (3)-1,2,4-oxadiazolyl, (4) —(C1-C2)alkyl-pyridinyl, (5)—(C1-C2)alkyl-pyrazolinyl, and (6) —(C1-C2)alkyl-1,2,4-oxadiazolyl,where the pyridinyl, pyrazolinyl, and −1,2,4-oxadiazolyl, isunsubstituted or substited with one L¹ group; R¹ is independentlyselected from the group consisting halogen, (C₁-C6)alkyl, —CN, —CF₃,—O-(C1-C6)alkyl, —O-(halo(C1-C6)alkyl), —C(O)—O—(C1-C6 )-OH-substituted(C1-C4)alkyl, halo(C1-C6)alkyl, —(C1-C4)alkoxy—OH,—(C1-C4)alkoxy(C1-C4)alkoxy and —S(O)₂(C1-C6)alkyl; n is 0, 1, 2, or 3;Ar is selected from the group consisting of phenyl optionallysubstituted with 1 or 2 L² groups, and pyridyl optionally substitutedwith 1 or 2 L² groups;

L¹ is independently selected from the group consisting of —OCH₃, —NH₂,═O, and (C1-C5)alkyl; and L² is independently selected from the groupconsisting of halogen, (C1-C6)alkyl, —CN, —CF₃, —O—(C1-C6)alkyl,—O-(halo(C1-C6)alkyl), —C(O)—O—(C1-C6)alkyl,—OH-substituted(C1-C6)alkyl, halo(C1-C6)alkyl, —OH-substituted(C1-C4)alkoxy, —(C1-C4)alkoxy(C1-C4)alkoxy and —S(O)₂(C1-C6)alkyl.

In some embodiments, the GSI is a compound described in U.S. Pat. No.9,226,927 (e.g., compound 4, 8a, 8b, 11, 14, 25a, 25b, 25c, 25d, 25e,25f, 25g, 25h, 27a, or 27b). In some embodiments, the compound offormula (XIV) comprises a bridged n-bicyclic sulfonamide or apharmaceutically acceptable salt thereof. In some embodiments, the GSIis selected from:

and pharmaceutically acceptable salts thereof.

In some embodiments, the GSI is an antibody molecule that reduces theexpression and/or function of gamma secretase. In some embodiments, theGSI is an antibody molecule targeting a subunit of gamma secretase. Insome embodiments, the GSI is chosen from an anti-presenilin antibodymolecule, an anti-nicastrin antibody molecule, an anti-APH-1 antibodymolecule, or an anti-PEN-2 antibody molecule.

Exemplary antibody molecules that target a subunit of gamma secretase(e.g., e.g., presenilin, nicastrin, APH-1, or PEN-2) are described inU.S. Pat. Nos. 8,394,376, 8,637,274, and 5,942,400.

In one aspect, the disclosure provides a method for treating subjectshaving a B cell condition or disorder, comprising administering to thesubject an effective amount of: (i) a MBM, and (ii) a gamma secretasemodulator (e.g., a GSI). Exemplary B cell conditions or disorders thatcan be treated with the combination of a MBM and a gamma secretasemodulator include multiple myeloma, Waldenstrom's macroglobulinemia,chronic lymphocytic leukemia, B cell non-Hodgkin's lymphoma,plasmacytoma, Hodgkins' lymphoma, follicular lymphomas, smallnon-cleaved cell lymphomas, endemic Burkitt's lymphoma, sporadicBurkitt's lymphoma, marginal zone lymphoma, extranodal mucosa-associatedlymphoid tissue lymphoma, nodal monocytoid B cell lymphoma, spleniclymphoma, mantle cell lymphoma, large cell lymphoma, diffuse mixed celllymphoma, immunoblastic lymphoma, primary mediastinal B cell lymphoma,pulmonary B cell angiocentric lymphoma, small lymphocytic lymphoma, Bcell proliferations of uncertain malignant potential, lymphomatoidgranulomatosis, post-transplant lymphoproliferative disorder, animmunoregulatory disorder, rheumatoid arthritis, myasthenia gravis,idiopathic thrombocytopenia purpura, anti-phospholipid syndrome, Chagas'disease, Grave's disease, Wegener's granulomatosis, poly-arteritisnodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiplesclerosis, anti-phospholipid syndrome, ANCA associated vasculitis,Goodpasture's disease, Kawasaki disease, autoimmune hemolytic anemia,rapidly progressive glomerulonephritis, heavy-chain disease, primary orimmunocyte-associated amyloidosis, and monoclonal gammopathy ofundetermined significance.

In some embodiments, the gamma secretase modulator is a gamma secretasemodulator described in WO 2017/019496. In some embodiments, the gammasecretase modulator is γ-secretase inhibitor I (GSI I)Z-Leu-Leu-Norleucine; γ-secretase inhibitor II (GSI II); γ-secretaseinhibitor III (GSI III), N-Benzyloxycarbonyl-Leu- leucinal,N-(2-Naphthoyl)-Val-phenylalaninal; γ-secretase inhibitor IV (GSI IV);y-secretase inhibitor V (GSI V), N-Benzyloxycarbonyl-Leu-phenylalaninal;γ-secretase inhibitor VI (GSI VI),1-(S)-endo-N-(1,3,3)-Trimethylbicyclo[2.2.1]hept-2-yl)-4-fluorophenylSulfonamide; γ-secretase inhibitor VII (GSI VII),Menthyloxycarbonyl-LL-CHO; γ-secretase inhibitor IX (GSI IX), (DAPT),N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-Butyl Ester;γ-secretase inhibitor X (GSI X), {1 S-Benzyl-4R-[1-(1S- carbamoyl-2-phenethylcarbamoyl)-1S-3-methylbutylcarb-amoyl]-2R-hydroxy-5-phenylpentyl}carbamic Acidtert-butyl Ester; γ-secretase inhibitor XI (GSI XI),7-Amino-4-chloro-3-methoxyisocoumarin; γ-secretase inhibitor XII (GSIXII), Z-Ile-Leu-CHO; γ-secretase inhibitor XIII (GSI XIII),Z-Tyr-Ile-Leu-CHO; γ-secretase inhibitor XIV (GSI XIV),Z-Cys(t-Bu)-Ile-Leu-CHO; γ-secretase inhibitor XVI (GSI XVI), N-[N-3,5-Difluorophenacetyl]-L-alanyl-S-phenylglycine Methyl Ester; γ-secretaseinhibitor XVII (GSI XVII); γ-secretase inhibitor XIX (GSI XIX),benzo[e][I,4]diazepin-3-yl)- butyramide; γ-secretase inhibitor XX (GSIXX), (S,S)-2-[2-(3,5- Difluorophenyl)acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7- yl)propionamide; γ-secretase inhibitorXXI (GSI XXI),(S,S)-2-[2-(3,5-Difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2-,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;Gamma40 secretase inhibitor I,N-trans-3,5-Dimethoxycinnamoyl-Ile-leucinal; Gamma40 secretase inhibitorII, N-tert-Butyloxycarbonyl-Gly-Val-Valinal; Isovaleryl-VV-Sta-A-Sta-OCH₃; MK-0752 (Merck); MRK-003 (Merck);semagacestat/LY450139 (Eli Lilly); RO4929097; PF-03084014; BMS-708163;MPC-7869 (γ-secretase modifier), YO-01027 (Dibenzazepine); LY411575 (EliLilly and Co.); L-685458 (Sigma-Aldrich); BMS-289948(4-chloro-N-(2,5-difluorophenyl)-N-((IR)-{4-fluoro-2-[3-(1H-imidazol-1-yl)propyl]phenyl}ethyl)benzenesulfonamidehydrochloride); or BMS-299897(4-[2-((IR)-1-{[(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)-5-fluorophenyljbutanoicacid) (Bristol Myers Squibb).

In some embodiments, a MBM can be used in combination with a member ofthe thalidomide class of compounds. Members of the thalidomide class ofcompounds include, but are not limited to, lenalidomide (CC-5013),pomalidomide (CC-4047 or ACTIMID), thalidomide, and salts andderivatives thereof. In some embodiments, the compound can be a mixtureof one, two, three, or more members of the thalidomide class ofcompounds. Thalidomide analogs and immunomodulatory properties ofthalidomide analogs are described in Bodera and Stankiewicz, Recent PatEndocr Metab Immune Drug Discov. 2011 Sep; 5(3):192-6. The structuralcomplex of thalidomide analogs and the E3 ubiquitin is described inGandhi et al., Br J Haematol. 2014 Mar; 164(6):811-21. The modulation ofthe E3 ubiquitin ligase by thalidomide analogs is described in Fischeret al., Nature. 2014 Aug. 7; 512(7512):49-53.

In some embodiments, the member of the thalidomide class of compoundscomprises a compound of Formula (I):

or a pharmaceutically acceptable salt, ester, hydrate, solvate, ortautomer thereof, where:

X is O or S;

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl, each of which isoptionally substituted by one or more R⁴;

each of R^(2a) and R^(2b) is independently hydrogen or C₁-C₆ alkyl; orR^(2a) and R^(2b) together with the carbon atom to which they areattached form a carbonyl group or a thiocarbonyl group;

each of R³ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ heteroalkyl, halo, cyano, —C(O)R^(A), —C(O)OR^(B), —OR^(B),—N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R^(C))C(O)R^(A),—S(O)_(x)R^(E), —S(O)_(x)N(R^(C))(R^(D)), or —N(R^(C))S(O)_(x)R^(E),where each alkyl, alkenyl, alkynyl, and heteroalkyl is independently andoptionally substituted with one or more R⁶;

each R⁴ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ heteroalkyl, halo, cyano, oxo, —C(O)R^(A), —C(O)OR^(B), —OR^(B),—N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R^(C))C(O)R^(A),—S(O)_(x)R^(E), —S(O)_(x)N(R^(C))(R^(D)), —N (R^(C))S(O)_(x)R^(E),carbocyclyl, heterocyclyl, aryl, or heteroaryl, where each alkyl,alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently and optionally substituted with one or moreR⁷;

each of R^(A), R^(B), R^(C), R^(D), and R^(E) is independently hydrogenor C₁-C₆ alkyl;

each R⁶ is independently C₁-C₆ alkyl, oxo, cyano, —OR^(B),—N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R^(C))C(O)R^(A), aryl, orheteroaryl, where each aryl and heteroaryl is independently andoptionally substituted with one or more R⁸;

each R⁷ is independently halo, oxo, cyano, —OR^(B), —N(R^(C))(R^(D)),—C(O)N(R^(C))(R^(D)), or —N(R^(C))C(O)R^(A);

each R⁸ is independently C₁-C₆ alkyl, cyano, —OR^(B), —N(R^(C))(R^(D)),—C(O)N(R^(C))(R^(D)), or —N(R^(C))C(O)R^(A);

n is 0, 1, 2, 3 or 4; and

x is 0, 1, or 2.

In some embodiments, X is O.

In some embodiments, R¹ is heterocyclyl. In some embodiments, R¹ is a6-membered heterocyclyl or a 5-membered heterocyclyl. In someembodiments, R¹ is a nitrogen-containing heterocyclyl. In someembodiments, R¹ is piperidinyl (e.g., piperidine-2,6-dionyl).

In some embodiments, each of R^(2a) and R^(2b) is independentlyhydrogen. In some embodiments, R^(2a) and R^(2b) together with thecarbon to which they are attached form a carbonyl group.

In some embodiments, R³ is C₁-C₆ heteroalkyl, —N(R^(C))(R^(D)) or—N(R^(C))C(O)R^(A). In some embodiments, R³ is C₁-C₆ heteroalkyl (e.g.,CH₂NHC(O)CH₂-phenyl-t-butyl), —N(R^(C))(R^(D)) (e.g., NH₂), or—N(R^(C))C(O)R^(A) (e.g., NHC(O)CH₃).

In an embodiment, X is O. In an embodiment, R¹ is heterocyclyl (e.g.,piperidine-2,6-dionyl). In an embodiment, each of R^(2a) and R^(2b) isindependently hydrogen. In an embodiment, n is 1. In an embodiment, R³is —N(R^(C))(R^(D)) (e.g., —NH₂). In an embodiment, the compoundcomprises lenalidomide, e.g.,3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or apharmaceutically acceptable salt thereof. In an embodiment, the compoundis lenalidomide, e.g., according to the following formula:

In an embodiment, X is O. In an embodiment, R¹ is heterocyclyl (e.g.,piperidinyl-2,6-dionyl). In some embodiments, R^(2a) and R^(2b) togetherwith the carbon to which they are attached form a carbonyl group. In anembodiment, n is 1. In an embodiment, R³ is —N(R^(C))(R^(D)) (e.g.,—NH₂). In an embodiment, the compound comprises pomalidomide, e.g.,4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or apharmaceutically acceptable salt thereof. In an embodiment, the compoundis pomalidomide, e.g., according to the following formula:

In an embodiment, X is O. In an embodiment, R¹ is heterocyclyl (e.g.,piperidinyl-2,6-dionyl). In an embodiment, R^(2a) and R^(2b) togetherwith the carbon to which they are attached form a carbonyl group. In anembodiment, n is 0. In an embodiment, the compound comprisesthalidomide, e.g., 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, ora pharmaceutically acceptable salt thereof. In an embodiment, theproduct is thalidomide, e.g., according to the following formula:

In an embodiment, X is O. In an embodiment, R¹ is heterocyclyl (e.g.,piperidine-2,6-dionyl). In an embodiment, each of R^(2a) and R^(2b) isindependently hydrogen. In an embodiment, n is 1. In an embodiment, R³is C₁-C₆ heteroalkyl (e.g., CH₂NHC(O)CH₂-phenyl-t-butyl) In anembodiment, the compound comprises2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide,or a pharmaceutically acceptable salt thereof. In an embodiment, thecompound has the structure as shown in the following formula:

In some embodiments, the compound is a compound of Formula (I-a):

or a pharmaceutically acceptable salt, ester, hydrate, or tautomerthereof, where:

Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl, each of whichoptionally substituted with one or more R⁴;

M is absent, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆heteroalkyl, where each alkyl, alkenyl, alkynyl, and heteroalkyl isoptionally substituted with one or more R⁴;

each of R^(2a) and R^(2b) is independently hydrogen or C₁-C₆ alkyl; orR^(2a) and R^(2b) together with the carbon atom to which they areattached to form a carbonyl group or thiocarbonyl group;

R^(3a) is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆heteroalkyl, halo, cyano, —C(O)R^(A), —C(O)OR^(B), —OR^(B),—N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R^(C))C(O)R^(A),—S(O)_(x)R^(E), —S(O)_(x)N(R^(C))(R^(D)), or —N(R^(C))S(O)_(x)R^(E),where each alkyl, alkenyl, alkynyl, and heteroalkyl is optionallysubstituted with one or more R⁶;

each of R³ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ heteroalkyl, halo, cyano, —C(O)R^(A), —C(O)OR^(B), —OR^(B),—N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R^(C))C(O)R^(A),—S(O)_(x)R^(E) , —S(O)_(x)N(R^(C))(R^(D)), or —N (R^(C))S(O)_(x)R^(E),where each alkyl, alkenyl, alkynyl, and heteroalkyl is independently andoptionally substituted with one or more R⁶;

each R⁴ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ heteroalkyl, halo, cyano, oxo, —C(O)R^(A), —C(O)OR^(B), —OR^(B),—N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R^(C))C(O)R^(A),S(O)_(x)R^(E), —S(O)_(x)N(R^(C))(R^(D)), —N (R^(C))S(O)_(x)R^(E),carbocyclyl, heterocyclyl, aryl, or heteroaryl, where each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl isindependently and optionally substituted with one or more R⁷;

each of R^(A), R^(B), R^(C), R^(D), and R^(E) is independently hydrogenor C₁-C₆ alkyl; each R⁶ is independently C₁-C₆ alkyl, oxo, cyano,—OR^(B), —N(R^(C))(R^(D)), —C(O)N(R^(C))(R^(D)), —N(R9C(O)R^(A), aryl,or heteroaryl, where each aryl or heteroaryl is independently andoptionally substituted with one or more R⁸;

each R⁷ is independently halo, oxo, cyano, —OR^(B), —N(R^(C))(R^(D)),—C(O)N(R^(C))(R^(D)), or —N(R^(C))C(O)R^(A);

each R⁸ is independently C₁-C₆ alkyl, cyano, —OR^(B), —N(R^(C))(R^(D)),—C(O)N(R^(C))(R^(D)), or —N(R^(C))C(O)R^(A);

n is 0, 1, 2, or 3;

o is 0, 1, 2, 3, 4, or 5; and

x is 0, 1, or 2.

In some embodiments, X is O.

In some embodiments, M is absent.

In some embodiments, Ring A is heterocyclyl. In some embodiments, Ring Ais heterocyclyl, e.g., a 6-membered heterocyclyl or a 5-memberedheterocyclyl. In some embodiments, Ring A is a nitrogen-containingheterocyclyl. In some embodiments, Ring A is piperidinyl (e.g.,piperidine-2,6-dionyl).

In some embodiments, M is absent and Ring A is heterocyclyl (e.g.,piperidinyl, e.g., piperidine-2,6-dionyl).

In some embodiments, each of R^(2a) and R^(2b) is independentlyhydrogen. In some embodiments, R^(2a) and R^(2b) together with thecarbon to which they are attached form a carbonyl group.

In some embodiments, R^(3a) is hydrogen, —N(R^(C))(R^(D)) or—N(R9C(O)RA. In some embodiments, R^(3a) is hydrogen. In someembodiments, R^(3a) is —N(R^(C))(R^(D)) (e.g., —NH₂). In someembodiments, R^(3a) is —N(R^(C))C(O)R^(A) (e.g, NHC(O)CH₃).

In some embodiments, R³ is C₁-C₆ heteroalkyl (e.g.,CH₂NHC(O)CH₂-phenyl-t-butyl). In some embodiments, n is 0 or 1. In someembodiments, n is 0. In some embodiments, n is 1.

The compound can comprise one or more chiral centers or ex ist as one ormore stereoisomers. In some embodiments, the compound comprises a singlechiral center and is a mixture of stereoisomers, e.g., an R stereoisomerand an S stereoisomer. In some embodiments, the mixture comprises aratio of R stereoisomers to S stereoisomers, for example, about a 1:1ratio of R stereoisomers to S stereoisomers (i.e., a racemic mixture).In some embodiments, the mixture comprises a ratio of R stereoisomers toS stereoisomers of about 51:49, about 52:48, about 53:47, about 54:46,about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about80:20, about 85:15, about 90:10, about 95:5, or about 99:1. In someembodiments, the mixture comprises a ratio of S stereoisomers to Rstereoisomers of about 51:49, about 52:48, about 53:47, about 54:46,about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about80:20, about 85:15, about 90:10, about 95:5, or about 99:1. In someembodiments, the compound is a single stereoisomer of Formula (I) orFormula (I-a), e.g., a single R stereoisomer or a single S stereoisomer.

In some embodiments, the MBM is administered in combination with akinase inhibitor. In one embodiment, the kinase inhibitor is aPI3-kinase inhibitor, e.g., CLR457, BGT226, or BYL719. In oneembodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., a CDK4inhibitor described herein, e.g., a CDK4/6 inhibitor, such as, e.g.,6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one,hydrochloride (also referred to as palbociclib or PD0332991). In oneembodiment, the kinase inhibitor is a BTK inhibitor, e.g., a BTKinhibitor described herein, such as, e.g., ibrutinib. In one embodiment,the kinase inhibitor is an mTOR inhibitor, e.g., an mTOR inhibitordescribed herein, such as, e.g., rapamycin, a rapamycin analog, OSI-027.The mTOR inhibitor can be, e.g., an mTORC1 inhibitor and/or an mTORC2inhibitor, e.g., an mTORC1 inhibitor and/or mTORC2 inhibitor describedherein. In one embodiment, the kinase inhibitor is a MNK inhibitor,e.g., a MNK inhibitor described herein, such as, e.g.,4-amino-5-(4-fluoroanilino)-pyrazolo [3,4-d] pyrimidine. The MNKinhibitor can be, e.g., a MNK1a, MNK1b, MNK2a and/or MNK2b inhibitor. Inone embodiment, the kinase inhibitor is a dual P13K/mTOR inhibitordescribed herein, such as, e.g., PF-04695102. In one embodiment, thekinase inhibitor is a DGK inhibitor, e.g., a DGK inhibitor describedherein, such as, e.g., DGKinh1 (D5919) or DGKinh2 (D5794).

In one embodiment, the kinase inhibitor is a BTK inhibitor selected fromibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224;CC-292; ONO-4059; CNX-774; and LFM-A13. In an embodiment, the BTKinhibitor does not reduce or inhibit the kinase activity ofinterleukin-2-inducible kinase (ITK), and is selected from GDC-0834;RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; andLFM-A13.

In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g.,ibrutinib (PCI-32765). In some embodiments, a MBM is administered to asubject in combination with ibrutinib (also called PCI-32765) (e.g., toa subject having CLL, MCL, or SLL). For example, the subject can have adeletion in the short arm of chromosome 17 (del(17p), e.g., in aleukemic cell). In other examples, the subject does not have a del(17p).In some embodiments, the subject has relapsed CLL or SLL, e.g., thesubject has previously been administered a cancer therapy (e.g.,previously been administered one, two, three, or four prior cancertherapies). In some embodiments, the subject has refractory CLL or SLL.In other embodiments, the subject has follicular lymphoma, e.g., relapseor refractory follicular lymphoma. In some embodiments, ibrutinib isadministered at a dosage of about 300-600 mg/day (e.g., about 300-350,350-400, 400-450, 450-500, 500-550, or 550-600 mg/day, e.g., about 420mg/day or about 560 mg/day), e.g., orally. In some embodiments, theibrutinib is administered at a dose of about 250 mg, 300 mg, 350 mg, 400mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580mg, 600 mg (e.g., 250 mg, 420 mg or 560 mg) daily for a period of time,e.g., daily for 21 day cycle, or daily for 28 day cycle. In oneembodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles ofibrutinib are administered. In some embodiments, ibrutinib isadministered in combination with rituximab. See, e.g., Burger et al.(2013) Ibrutinib In Combination With Rituximab (iR) Is Well Toleratedand Induces a High Rate Of Durable Remissions In Patients With High-RiskChronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase IITrial In 40 Patients, Abstract 675 presented at 55th ASH Annual Meetingand Exposition, New Orleans, LA 7-10 Dec. Without being bound by theory,it is thought that the addition of ibrutinib enhances the T cellproliferative response and can shift T cells from a T-helper-2 (Th2) toT- helper-1 (Th1) phenotype. Th1 and Th2 are phenotypes of helper Tcells, with Th1 versus Th2 directing different immune response pathways.A Th1 phenotype is associated with proinflammatory responses, e.g., forkilling cells, such as intracellular pathogens/viruses or cancerouscells, or perpetuating autoimmune responses. A Th2 phenotype isassociated with eosinophil accumulation and anti-inflammatory responses.

In some embodiments, the MBM is administered in combination with aninhibitor of Epidermal Growth Factor Receptor (EGFR).

In some embodiments, the EGFR inhibitor is (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) or a compound disclosed in PCT Publication No. WO2013/184757.

In some embodiments, the EGFR inhibitor, e.g.,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) or a compound disclosed in PCT Publication No. WO2013/184757, is administered at a dose of 150-250 mg, e.g., per day. Insome embodiments, the EGFR inhibitor, e.g.,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (Compound A40) or acompound disclosed in PCT Publication No. WO 2013/184757, isadministered at a dose of about 150, 200, or 250 mg, or about 150-200 or200-250 mg.

In some embodiments, the EGFR inhibitor,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40), or a compound disclosed in PCT Publication No. WO2013/184757, is a covalent, irreversible tyrosine kinase inhibitor. Incertain embodiments, the EGFR inhibitor,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40), or a compound disclosed in PCT Publication No. WO2013/184757 inhibits activating EGFR mutations (L858R, ex19del). Inother embodiments, the EGFR inhibitor,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40), or a compound disclosed in PCT Publication No. WO2013/184757 does not inhibit, or does not substantially inhibit, wild-type (wt) EGFR. Compound A40 has shown efficacy in EGFR mutant NSCLCpatients. In some embodiments, the EGFR inhibitor,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40), or a compound disclosed in PCT Publication No. WO2013/184757 also inhibits one or more kinases in the TEC family ofkinases. The Tec family kinases include, e.g., ITK, BMX, TEC, RLK, andBTK, and are central in the propogation of T-cell receptor and chemokinereceptor signaling (Schwartzberg et al. (2005) Nat. Rev. lmmunol. p.284-95). For example, Compound A40 can inhibit ITK with a biochemicalIC50 of 1.3 nM. ITK is a critical enzyme for the survival of Th2 cellsand its inhibition results in a shift in the balance between Th2 and Th1cells.

In some embodiments, the EGFR inhibitor is chosen from one of more oferlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804,nimotuzumab, or R05083945.

In some embodiments, the MBM is administered in combination with anadenosine A2A receptor (A2AR) antagonist. Exemplary A2AR antagonistsinclude, e.g., PBF509 (Palobiofarma/Novartis), CPI444/V81444(Corvus/Genentech), AZD4635/HTL-1071 (AstraZeneca/Heptares), Vipadenant(Redox/Juno), GBV-2034 (Globavir), AB928 (Arcus Biosciences),Theophylline, Istradefylline (Kyowa Hakko Kogyo), Tozadenant/SYN-115(Acorda), KW-6356 (Kyowa Hakko Kogyo), ST-4206 (Leadiant Biosciences),Preladenant/SCH 420814 (Merck/Schering), and NIR178 (Novartis).

In certain embodiments, the A2AR antagonist is PBF509. PBF509 and otherA2AR antagonists are disclosed in US 8,796,284 and WO 2017/025918. Incertain embodiments, the A2AR antagonist is5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidine-4-amine. In certainembodiments, the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is CPI444/V81444. CPI-444and other A2AR antagonists are disclosed in WO 2009/156737. In certainembodiments, the A2AR antagonist is(S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine.In certain embodiments, the A2AR antagonist is(R)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine,or racemate thereof. In certain embodiments, the A2AR antagonist is7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine.In certain embodiments, the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is AZD4635/HTL-1071. A2ARantagonists are disclosed in WO 2011/095625. In certain embodiments, theA2AR antagonist is6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.In certain embodiments, the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is ST-4206 (LeadiantBiosciences). In certain embodiments, the A2AR antagonist is an A2ARantagonist described in U.S. Pat. No. 9,133,197. In certain embodiments,the A2AR antagonist has the following structure:

In certain embodiments, the A2AR antagonist is an A2AR antagonistdescribed in U.S. Pat. Nos. 8,114,845, 9,029,393, US20170015758, orUS20160129108.

In certain embodiments, the A2AR antagonist is istradefylline (CASRegistry Number: 155270-99-8). Istradefylline is also known as KW-6002or8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione.Istradefylline is disclosed, e.g., in LeWitt et al. (2008) Annals ofNeurology 63 (3): 295-302).

In certain embodiments, the A2aR antagonist is tozadenant (Biotie).Tozadenant is also known as SYN115 or4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)-4-methylpiperidine-1-carboxamide.Tozadenant blocks the effect of endogenous adenosine at the A2areceptors, resulting in the potentiation of the effect of dopamine atthe D2 receptor and inhibition of the effect of glutamate at the mGluR5receptor. In some embodiments, the A2aR antagonist is preladenant (CASRegistry Number: 377727-87-2). Preladenant is also known as SCH 420814or2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine.Preladenant was developed as a drug that acted as a potent and selectiveantagonist at the adenosine A2A receptor.

In certain embodiments, the A2aR antagonist is vipadenan. Vipadenan isalso known as BIIB014, V2006, or3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)]triazolo[4,5-d]pyrimidin-5-amine.

Other exemplary A2aR antagonists include, e.g., ATL-444, MSX-3,SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835,CGS-15943, or ZM-241,385.

In some embodiments, the A2aR antagonist is an A2aR pathway antagonist(e.g., a CD-73 inhibitor, e.g., an anti-CD73 antibody) is MED19447.MED19447 is a monoclonal antibody specific for CD73. Targeting theextracellular production of adenosine by CD73 may reduce theimmunosuppressive effects of adenosine. MED19447 was reported to have arange of activities, e.g., inhibition of CD73 ectonucleotidase activity,relief from AMP-mediated lymphocyte suppression, and inhibition ofsyngeneic tumor growth. MED19447 can drive changes in both myeloid andlymphoid infiltrating leukocyte populations within the tumormicroenvironment. These changes include, e.g., increases in CD8 effectorcells and activated macrophages, as well as a reduction in theproportions of myeloid-derived suppressor cells (MDSC) and regulatory Tlymphocytes.

In some embodiments, the MBM is administered in combination with aCAR-expressing cell therapy such as a CD19 CAR-expressing cell therapy.

In one embodiment, the antigen binding domain of the CD19 CAR has thesame or a similar binding specificity as the FMC63 scFv fragmentdescribed in Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997).In one embodiment, the antigen binding domain of the CD19 CAR includesthe scFv fragment described in Nicholson et al. Mol. Immun. 34 (16-17):1157-1165 (1997).

In some embodiments, the CD19 CAR includes an antigen binding domain(e.g., a humanized antigen binding domain) according to Table 3 ofWO2014/153270. WO2014/153270 also describes methods of assaying thebinding and efficacy of various CAR constructs.

In one aspect, the parental murine scFv sequence is the CAR19 constructprovided in PCT publication WO2012/079000. In one embodiment, theanti-CD19 binding domain is a scFv described in WO2012/079000.

In one embodiment, the CAR molecule comprises the fusion polypeptidesequence provided as SEQ ID NO: 12 in PCT publication WO2012/079000,which provides an scFv fragment of murine origin that specifically bindsto human CD19.

In one embodiment, the CD19 CAR comprises an amino acid sequenceprovided as SEQ ID NO: 12 in PCT publication WO2012/079000.

In one embodiment, the CD19 CAR has the USAN designationTISAGENLECLEUCEL-T. In embodiments, CTL019 is made by a genemodification of T cells is mediated by stable insertion via transductionwith a self-inactivating, replication deficient Lentiviral (LV) vectorcontaining the CTL019 transgene under the control of the EF-1 alphapromoter. CTL019 can be a mixture of transgene positive and negative Tcells that are delivered to the subject on the basis of percenttransgene positive T cells.

In other embodiments, the CD19 CAR comprises an antigen binding domain(e.g., a humanized antigen binding domain) according to Table 3 ofWO2014/153270.

Humanization of murine CD19 antibody is desired for the clinicalsetting, where the mouse-specific residues can induce a human-anti-mouseantigen (HAMA) response in patients who receive CART19 treatment, i.e.,treatment with T cells transduced with the CAR19 construct. Theproduction, characterization, and efficacy of humanized CD19 CARsequences is described in International Application WO2014/153270,including Examples 1-5 (p. 115-159).

In some embodiments, CD19 CAR constructs are described in PCTpublication WO 2012/079000.

CD19 CAR constructs containing humanized anti-CD19 scFv domains aredescribed in PCT publication WO 2014/153270.

Any known CD19 CAR, e.g., the CD19 antigen binding domain of any knownCD19 CAR, in the art can be used in accordance with the presentdisclosure. For example, LG-740; CD19 CAR described in the U.S. Pat.Nos. 8,399,645, 7,446,190; Xu et al., Leuk Lymphoma. 201354(2):255-260(2012); Cruz et al., Blood 122(17):2965-2973 (2013);Brentjens et al., Blood, 118(18):4817-4828 (2011); Kochenderfer et al.,Blood 116(20):4099-102 (2010); Kochenderfer et al., Blood 122(25):4129-39(2013); and 16th Annu Meet Am Soc Gen Cell Ther (ASGCT) (May15-18, Salt Lake City) 2013, Abst 10.

Exemplary CD19 CARs include CD19 CARs described herein, or an anti-CD19CAR described in Xu et al. Blood 123.24(2014):3750-9; Kochenderfer etal. Blood 122.25(2013):4129-39, Cruz et al. Blood 122.17(2013):2965-73,NCT00586391, NCT01087294, NCT02456350, NCT00840853, NCT02659943,NCT02650999, NCT02640209, NCT01747486, NCT02546739, NCT02656147,NCT02772198, NCT00709033, NCT02081937, NCT00924326, NCT02735083,NCT02794246, NCT02746952, NCT01593696, NCT02134262, NCT01853631,NCT02443831, NCT02277522, NCT02348216, NCT02614066, NCT02030834,NCT02624258, NCT02625480, NCT02030847, NCT02644655, NCT02349698,NCT02813837, NCT02050347, NCT01683279, NCT02529813, NCT02537977,NCT02799550, NCT02672501, NCT02819583, NCT02028455, NCT01840566,NCT01318317, NCT01864889, NCT02706405, NCT01475058, NCT01430390,NCT02146924, NCT02051257, NCT02431988, NCT01815749, NCT02153580,NCT01865617, NCT02208362, NCT02685670, NCT02535364, NCT02631044,NCT02728882, NCT02735291, NCT01860937, NCT02822326, NCT02737085,NCT02465983, NCT02132624, NCT02782351, NCT01493453, NCT02652910,NCT02247609, NCT01029366, NCT01626495, NCT02721407, NCT01044069,NCT00422383, NCT01680991, NCT02794961, or NCT02456207.

In some embodiments, the MBM is administered in combination with a CD20inhibitor.

In one embodiment, the CD20 inhibitor is an anti-CD20 antibody orfragment thereof. In an embodiment, the antibody is a monospecificantibody and in another embodiment, the antibody is a bispecificantibody. In an embodiment, the CD20 inhibitor is a chimeric mouse/humanmonoclonal antibody, e.g., rituximab. In an embodiment, the CD20inhibitor is a human monoclonal antibody such as ofatumumab. In anembodiment, the CD20 inhibitor is a humanized antibody such asocrelizumab, veltuzumab, obinutuzumab, ocaratuzumab, or PRO131921(Genentech). In an embodiment, the CD20 inhibitor is a fusion proteincomprising a portion of an anti-CD20 antibody, such as TRU-015 (TrubionPharmaceuticals).

In some embodiments, the MBM is administered in combination with a CD22CAR-expressing cell therapy (e.g., cells expressing a CAR that binds tohuman CD22).

In some embodiments, the MBM is administered in combination with a CD22inhibitor. In some embodiments, the CD22 inhibitor is a small moleculeor an anti-CD22 antibody molecule. In some embodiments, the antibody isa monospecific antibody, optionally conjugated to a second agent such asa chemotherapeutic agent. For instance, in an embodiment, the antibodyis an anti-CD22 monoclonal antibody-MMAE conjugate (e.g., DCDT2980S). Inan embodiment, the antibody is an scFv of an anti-CD22 antibody, e.g.,an scFv of antibody RFB4. This scFv can be fused to all of or a fragmentof Pseudomonas exotoxin-A (e.g., BL22). In an embodiment, the antibodyis a humanized anti-CD22 monoclonal antibody (e.g., epratuzumab). In anembodiment, the antibody or fragment thereof comprises the Fv portion ofan anti-CD22 antibody, which is optionally covalently fused to all or afragment or (e.g., a 38 KDa fragment of) Pseudomonas exotoxin-A (e.g.,moxetumomab pasudotox). In an embodiment, the anti-CD22 antibody is ananti-CD19/CD22 bispecific antibody, optionally conjugated to a toxin.For instance, in one embodiment, the anti-CD22 antibody comprises ananti-CD19/CD22 bispecific portion, (e.g., two scFv ligands, recognizinghuman CD19 and CD22) optionally linked to all of or a portion ofdiphtheria toxin (DT), e.g., first 389 amino acids of diphtheria toxin(DT), DT 390, e.g., a ligand-directed toxin such as DT2219ARL). Inanother embodiment, the bispecific portion (e.g., anti-CD19/anti-CD22)is linked to a toxin such as deglycosylated ricin A chain (e.g.,Combotox).

In some embodiments, the CD22 inhibitor is a multispecific antibodymolecule, e.g., a bispecific antibody molecule, e.g., a bispecificantibody molecule that binds to CD20 and CD3. Exemplary bispecificantibody molecules that bind to CD20 and CD3 are disclosed inWO2016086189 and WO2016182751. In some embodiments, the bispecificantibody molecule that binds to CD20 and CD3 is XENP13676 as disclosedin FIG. 74 , SEQ ID NOs: 323, 324, and 325 of WO2016086189.

In some embodiments, the CD22 CAR-expressing cell therapy includes anantigen binding domain according to WO2016/164731.

In some embodiments, the MBM is administered in combination with a FCRL2or FCRL5 inhibitor. In some embodiments, the FCRL2 or FCRL5 inhibitor isan anti-FCRL2 antibody molecule, e.g., a bispecific antibody molecule,e.g., a bispecific antibody that binds to FCRL2 and CD3. In someembodiments, the FCRL2 or FCRL5 inhibitor is an anti-FCRL5 antibodymolecule, e.g., a bispecific antibody molecule, e.g., a bispecificantibody that binds to FCRL5 and CD3. In some embodiments, the FCRL2 orFCRL5 inhibitor is a FCRL2 CAR-expressing cell therapy. In someembodiments, the FCRL2 or FCRL5 inhibitor is a FCRL5 CAR- expressingcell therapy.

Exemplary anti-FCRL5 antibody molecules are disclosed in US20150098900,US20160368985, WO2017096120 (e.g., antibodies ET200-001, ET200-002,ET200-003, ET200-006, ET200-007, ET200-008, ET200-009, ET200-010,ET200-011, ET200-012, ET200-013, ET200-014, ET200-015, ET200-016,ET200-017, ET200-018, ET200-019, ET200-020, ET200-021, ET200-022,ET200-023, ET200-024, ET200-025, ET200-026, ET200-027, ET200-028,ET200-029, ET200-030, ET200-031, ET200-032, ET200-033, ET200-034,ET200-035, ET200-037, ET200-038, ET200-039, ET200-040, ET200-041,ET200-042, ET200-043, ET200-044, ET200-045, ET200-069, ET200-078,ET200-079, ET200-081, ET200-097, ET200-098, ET200-099, ET200-100,ET200-101, ET200-102, ET200-103, ET200-104, ET200-105, ET200- 106,ET200-107, ET200-108, ET200-109, ET200-110, ET200-111, ET200-112,ET200-113, ET200-114, ET200-115, ET200-116, ET200-117, ET200-118,ET200-119, ET200-120, ET200- 121, ET200-122, ET200-123, ET200-125,ET200-005 and ET200-124 disclosed in WO2017096120).

Exemplary FCRLS CAR molecules are disclosed in WO2016090337.

In some embodiments, the MBM is administered in combination with anIL15/IL-15Ra complex. In some embodiments, the 1L-15/IL-15Ra complex ischosen from NIZ985 (Novartis), ATL-803 (Altor) or CYP0150 (Cytune).

In some embodiments, the 1L-15/IL-15Ra complex comprises human IL-15complexed with a soluble form of human IL-15Ra. The complex can compriseIL-15 covalently or noncovalently bound to a soluble form of IL-15Ra. Ina particular embodiment, the human IL-15 is noncovalently bonded to asoluble form of IL-15Ra. In a particular embodiment, the human IL-15 ofthe composition comprises an amino acid sequence as described in WO2014/066527and the soluble form of human IL-15Ra comprises an amino acidsequence as described in WO 2014/066527. The molecules described hereincan be made by vectors, host cells, and methods described in WO2007/084342.

In some embodiments, the IL-15/IL-15Ra complex is ALT-803, anIL-15/IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu/Fc solublecomplex). ALT-803 is disclosed in WO 2008/143794.

In some embodiments, the IL-15/IL-15Ra complex comprises IL-15 fused tothe sushi domain of IL-15Ra (CYP0150, Cytune). The sushi domain ofIL-15Ra refers to a domain beginning at the first cysteine residue afterthe signal peptide of IL-15Ra, and ending at the fourth cysteine residueafter the signal peptide. The complex of IL-15 fused to the sushi domainof IL-15Ra is disclosed in WO 2007/04606 and WO 2012/175222.

In some embodiments, the MBM is administered in combination with a PD-1inhibitor. In some embodiments, the PD-1 inhibitor is chosen from PDR001(Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck &Co), Pidilizumab (CureTech), MED10680 (Medimmune), REGN2810 (Regeneron),TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108(Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). In oneembodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In oneembodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule asdescribed in US 2015/0210769.

In one embodiment, the anti-PD-1 antibody molecule is Nivolumab(Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538,BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD-1antibodies are disclosed in US 8,008,449 and WO 2006/121168. In oneembodiment, the anti-PD-1 antibody molecule comprises one or more of theCDR sequences (or collectively all of the CDR sequences), the heavychain or light chain variable region sequence, or the heavy chain orlight chain sequence of Nivolumab.

In one embodiment, the anti-PD-1 antibody molecule is Pembrolizumab(Merck & Co), also known as Lambrolizumab, MK-3475, MK03475, SCH-900475,or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosedin Hamid, O. et al. (2013) New England Journal of Medicine 369 (2):134-44, U.S. Pat. No. 8,354,509, and WO 2009/114335. In one embodiment,the anti-PD-1 antibody molecule comprises one or more of the CDRsequences (or collectively all of the CDR sequences), the heavy chain orlight chain variable region sequence, or the heavy chain or light chainsequence of Pembrolizumab.

In one embodiment, the anti-PD-1 antibody molecule is Pidilizumab(CureTech), also known as CT-011. Pidilizumab and other anti-PD-1antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy34(5): 409-18, U.S. Pat. Nos. 7,695,715, 7,332,582, and 8,686,119. Inone embodiment, the anti-PD-1 antibody molecule comprises one or more ofthe CDR sequences (or collectively all of the CDR sequences), the heavychain or light chain variable region sequence, or the heavy chain orlight chain sequence of Pidilizumab.

In one embodiment, the anti-PD-1 antibody molecule is MED10680(Medimmune), also known as AMP-514. MED10680 and other anti-PD-1antibodies are disclosed in U.S. Pat. No. 9,205,148 and WO 2012/145493.In one embodiment, the anti-PD-1 antibody molecule comprises one or moreof the CDR sequences (or collectively all of the CDR sequences), theheavy chain or light chain variable region sequence, or the heavy chainor light chain sequence of MED10680.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810(Regeneron). In one embodiment, the anti-PD-1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of REGN2810.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591(Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprisesone or more of the CDR sequences (or collectively all of the CDRsequences), the heavy chain or light chain variable region sequence, orthe heavy chain or light chain sequence of PF-06801591.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 orBGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of BGB-A317 or BGB-108.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210(Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, theanti-PD-1 antibody molecule comprises one or more of the CDR sequences(or collectively all of the CDR sequences), the heavy chain or lightchain variable region sequence, or the heavy chain or light chainsequence of INCSHR1210.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro),also known as ANB011. In one embodiment, the anti-PD-1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of TSR-042.

Further known anti-PD-1 antibodies include those described, e.g., in WO2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO2014/194302, WO 2014/209804, WO 2015/200119, U.S. Pat. Nos. 8,735,553,7,488,802, 8,927,697, 8,993,731, and 9,102,727.

In one embodiment, the anti-PD-1 antibody is an antibody that competesfor binding with, and/or binds to the same epitope on PD-1 as, one ofthe anti-PD-1 antibodies described herein.

In one embodiment, the PD-1 inhibitor is a peptide that inhibits thePD-1 signaling pathway, e.g., as described in U.S. pat. No. 8,907,053.In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., animmunoadhesin comprising an extracellular or PD-1 binding portion ofPD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of animmunoglobulin sequence). In one embodiment, the PD-1 inhibitor isAMP-224 (B7-DCIg (Amplimmune), e.g., disclosed in WO 2010/027827 and WO2011/066342).

In some embodiments, the MBM is administered in combination with a PD-L1inhibitor. In some embodiments, the PD-L1 inhibitor is chosen fromFAZ053 (Novartis), Atezolizumab (Genentech/Roche), Avelumab (MerckSerono and Pfizer), Durvalumab (Medlmmune/AstraZeneca), or BMS-936559(Bristol-Myers Squibb).

In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibodymolecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1antibody molecule as disclosed in US 2016/0108123.

In one embodiment, the anti-PD-L1 antibody molecule is Atezolizumab(Genentech/Roche), also known as MPDL3280A, RG7446, RO5541267,YW243.55.S70, or TECENTRIQ™. Atezolizumab and other anti-PD-L1antibodies are disclosed in U.S. Pat. No. 8,217,149. In one embodiment,the anti-PD-L1 antibody molecule comprises one or more of the CDRsequences (or collectively all of the CDR sequences), the heavy chain orlight chain variable region sequence, or the heavy chain or light chainsequence of Atezolizumab.

In one embodiment, the anti-PD-L1 antibody molecule is Avelumab (MerckSerono and Pfizer), also known as MSB0010718C. Avelumab and otheranti-PD-L1 antibodies are disclosed in WO 2013/079174. In oneembodiment, the anti-PD-L1 antibody molecule comprises one or more ofthe CDR sequences (or collectively all of the CDR sequences), the heavychain or light chain variable region sequence, or the heavy chain orlight chain sequence of Avelumab.

In one embodiment, the anti-PD-L1 antibody molecule is Durvalumab(Medlmmune/AstraZeneca), also known as MED14736. Durvalumab and otheranti-PD-L1 antibodies are disclosed in US 8,779,108. In one embodiment,the anti-PD-L1 antibody molecule comprises one or more of the CDRsequences (or collectively all of the CDR sequences), the heavy chain orlight chain variable region sequence, or the heavy chain or light chainsequence of Durvalumab.

In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559(Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 andother anti-PD-L1 antibodies are disclosed in U.S. Pat. No. 7,943,743 andWO 2015/081158. In one embodiment, the anti-PD-L1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of BMS-936559.

Further known anti-PD-L1 antibodies include those described, e.g., in WO2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO2014/055897, WO 2015/061668, WO 2013/079174, WO 2012/145493, WO2015/112805, WO 2015/109124, WO 2015/195163, U.S. Pat. Nos. 8,168,179,8,552,154, 8,460,927, and 9,175,082.

In some embodiments, the MBM is administered in combination with a LAG-3inhibitor. In some embodiments, the LAG-3 inhibitor is chosen fromLAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033(Tesaro).

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibodymolecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3antibody molecule as disclosed in US 2015/0259420.

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016(Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and otheranti-LAG-3 antibodies are disclosed in WO 2015/116539 and U.S. Pat. No.9,505,839. In one embodiment, the anti-LAG-3 antibody molecule comprisesone or more of the CDR sequences (or collectively all of the CDRsequences), the heavy chain or light chain variable region sequence, orthe heavy chain or light chain sequence of BMS-986016.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro).In one embodiment, the anti-LAG-3 antibody molecule comprises one ormore of the CDR sequences (or collectively all of the CDR sequences),the heavy chain or light chain variable region sequence, or the heavychain or light chain sequence of TSR-033.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 orGSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3antibodies are disclosed in WO 2008/132601 and U.S. Pat. No. 9,244,059.In one embodiment, the anti-LAG-3 antibody molecule comprises one ormore of the CDR sequences (or collectively all of the CDR sequences),the heavy chain or light chain variable region sequence, or the heavychain or light chain sequence of IMP731. In one embodiment, theanti-LAG-3 antibody molecule comprises one or more of the CDR sequences(or collectively all of the CDR sequences), the heavy chain or lightchain variable region sequence, or the heavy chain or light chainsequence of GSK2831781.

Further known anti-LAG-3 antibodies include those described, e.g., in WO2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO2015/200119, WO 2016/028672, U.S. Pat. Nos. 9,244,059, 9,505,839.

In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein,e.g., IMP321 (Prima BioMed), e.g., as disclosed in WO 2009/044273.

In some embodiments, the MBM is administered in combination with a TIM-3inhibitor. In some embodiments, the TIM-3 inhibitor is MBG453 (Novartis)or TSR-022 (Tesaro).

In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibodymolecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3antibody molecule as disclosed in US 2015/0218274.

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022(AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of TSR-022. In oneembodiment, the anti-TIM-3 antibody molecule comprises one or more ofthe CDR sequences (or collectively all of the CDR sequences), the heavychain or light chain variable region sequence, or the heavy chain orlight chain sequence of APE5137 or APE5121. APE5137, APE5121, and otheranti-TIM-3 antibodies are disclosed in WO 2016/161270.

In one embodiment, the anti-TIM-3 antibody molecule is the antibodyclone F38-2E2. In one embodiment, the anti-TIM-3 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of F38-2E2.

Further known anti-TIM-3 antibodies include those described, e.g., in WO2016/111947, WO 2016/071448, WO 2016/144803, U.S. Pat. No. 8,552,156,8,841,418, and 9,163,087.

In one embodiment, the anti-TIM-3 antibody is an antibody that competesfor binding with, and/or binds to the same epitope on TIM-3 as, one ofthe anti-TIM-3 antibodies described herein.

In some embodiments, the MBM is administered in combination with atransforming growth factor beta (TGF-β) inhibitor. In some embodiments,the TGF-β inhibitor is fresolimumab (CAS Registry Number: 948564-73-6).Fresolimumab is also known as GC1008. Fresolimumab is a human monoclonalantibody that binds to and inhibits TGF-beta isoforms 1, 2 and 3.Fresolimumab is disclosed, e.g., in WO 2006/086469, U.S. Pat. Nos.8,383,780, and 8,591,901.

In some embodiments, the TGF-13 inhibitor is XOMA 089. XOMA 089 is alsoknown as XPA.42.089. XOMA 089 is a fully human monoclonal antibody thatbinds and neutralizes TGF-beta 1 and 2 ligands, and is disclosed in PCTPublication No. WO 2012/167143.

In some embodiments, the MBM is administered in combination with ananti-CD73 antibody molecule. In one embodiment, an anti-CD73 antibodymolecule is a full antibody molecule or an antigen-binding fragmentthereof. In certain embodiments, the anti-CD73 antibody molecule bindsto a CD73 protein and reduces, e.g., inhibits or antagonizes, anactivity of CD73, e.g., human CD73.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2016/075099. In one embodiment, the anti-CD73antibody molecule is MEDI 9447, e.g., as disclosed in WO2016/075099.Alternative names for MEDI 9447 include clone 10.3 or 73combo3. MEDI9447 is an IgG1 antibody that inhibits, e.g., antagonizes, an activityof CD73. MEDI 9447 and other anti-CD73 antibody molecules are alsodisclosed in WO2016/075176 and US2016/0129108.

In one embodiment, the anti-CD73 antibody molecule comprises a heavychain variable domain, a light chain variable domain, or both, of MEDI9477.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2016/081748. In one embodiment, the anti-CD73antibody molecule is 11F11, e.g., as disclosed in WO2016/081748. 11F11is an IgG2 antibody that inhibits, e.g., antagonizes, an activity ofCD73. Antibodies derived from 11F11, e.g., CD73.4, and CD73.10; clonesof 11F11, e.g., 11F11-1 and 11F11-2; and other anti-CD73 antibodymolecules are disclosed in WO2016/081748 and U.S. Pat. No. 9,605,080.

In one embodiment, the anti-CD73 antibody molecule comprises a heavychain variable domain, a light chain variable domain, or both, of11F11-1 or 11F11-2.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in e.g., U.S. Pat. No. 9,605,080.

In one embodiment, the anti-CD73 antibody molecule is CD73.4, e.g., asdisclosed in U.S. Pat. No. 9,605,080. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of CD73.4.

In one embodiment, the anti-CD73 antibody molecule is CD73.10, e.g., asdisclosed in U.S. Pat. No. 9,605,080. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of CD73.10.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2009/0203538. In one embodiment, the anti-CD73antibody molecule is 067-213, e.g., as disclosed in WO2009/0203538.

In one embodiment, the anti-CD73 antibody molecule comprises a heavychain variable domain, a light chain variable domain, or both, of067-213.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in U.S. Pat. No. 9,090,697. In one embodiment, theanti-CD73 antibody molecule is TY, 23, e.g., as disclosed in U.S. Pat.No. 9,090,697. In one embodiment, the anti-CD73 antibody moleculecomprises a heavy chain variable domain, a light chain variable domain,or both, of TY, 23.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2016/055609. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti- CD73 antibody disclosed inWO2016/055609.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2016/146818. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti-CD73 antibody disclosed inWO2016/146818.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2004/079013. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti- CD73 antibody disclosed inWO2004/079013.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2012/125850. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti-CD73 antibody disclosed inWO2012/125850.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2015/004400. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti-CD73 antibody disclosed inWO2015/004400.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in WO2007/146968. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti-CDb 73 antibody disclosed inWO2007146968.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in US2007/0042392. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti-CD73 antibody disclosed inUS2007/0042392.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in US2009/0138977. In one embodiment, the anti-CD73antibody molecule comprises a heavy chain variable domain, a light chainvariable domain, or both, of an anti-CD73 antibody disclosed inUS2009/0138977.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in Flocke et al., Eur J Cell Biol. 1992 Jun;58(1):62-70. In one embodiment, the anti-CD73 antibody moleculecomprises a heavy chain variable domain, a light chain variable domain,or both, of an anti-CD73 antibody disclosed in Flocke et al., Eur J CellBiol. 1992 June; 58(1):62-70.

In one embodiment, the anti-CD73 antibody molecule is an anti-CD73antibody disclosed in Stagg et al., PNAS. 2010 Janiary 107(4):1547-1552. In some embodiments, the anti-CD73 antibody molecule is TY,23 or TY11.8, as disclosed in Stagg et al. In one embodiment, theanti-CD73 antibody molecule comprises a heavy chain variable domain, alight chain variable domain, or both, of an anti-CD73 antibody disclosedin Stagg et al.

In some embodiments, the MBM is administered in combination with aninterleukine-17 (IL-17) inhibitor.

In some embodiments, the IL-17 inhibitor is secukinumab (CAS RegistryNumbers: 875356-43-7 (heavy chain) and 875356-44-8 (light chain)).Secukinumab is also known as AIN457 and COSENTYX®. Secukinumab is arecombinant human monoclonal IgG1/K antibody that binds specifically toIL-17A. It is expressed in a recombinant Chinese Hamster Ovary (CHO)cell line. Secukinumab is described, e.g., in WO 2006/013107, U.S. Pat.No. 7,807,155, 8,119,131, 8,617,552, and EP 1776142.

In some embodiments, the IL-17 inhibitor is CJM112. CJM112 is also knownas XAB4. CJM112 is a fully human monoclonal antibody (e.g., of theIgG1/K isotype) that targets IL-17A. CJM112 is disclosed, e.g., in WO2014/122613.

CJM112 can bind to human, cynomolgus, mouse and rat IL-17A andneutralize the bioactivity of these cytokines in vitro and in vivo.IL-17A, a member of the IL-17 family, is a major proinflammatorycytokine that has been indicated to play important roles in many immunemediated conditions, such as psoriasis and cancers (Witowski et al.(2004) Cell Mol. Life Sci. p. 567-79; Miossec and Kolls (2012) Nat. Rev.Drug Discov. p. 763-76).

In some embodiments, the IL-17 inhibitor is ixekizumab (CAS RegistryNumber: 1143503-69-8). Ixekizumab is also known as LY2439821. Ixekizumabis a humanized IgG4 monoclonal antibody that targets IL-17A. Ixekizumabis described, e.g., in WO 2007/070750, U.S. Pat. Nos. 7,838,638, and8,110,191.

In some embodiments, the IL-17 inhibitor is brodalumab (CAS RegistryNumber: 1174395-19-7). Brodalumab is also known as AMG 827 or AM-14.Brodalumab binds to the interleukin-17 receptor A (IL-17RA) and preventsIL-17 from activating the receptor. Brodalumab is disclosed, e.g., in WO2008/054603, U.S. Pat. No. 7,767,206, 7,786,284, 7,833,527, 7,939,070,8,435,518, 8,545,842, 8,790,648, and 9,073,999.

In some embodiments, the MBM is administered in combination with aninterleukine-1 beta (IL-1[3) inhibitor.

In some embodiments, the IL-1β inhibitor is canakinumab. Canakinumab isalso known as ACZ885 or ILARIS®. Canakinumab is a human monoclonalIgG1/K antibody that neutralizes the bioactivity of human IL-1β.Canakinumab is disclosed, e.g., in WO 2002/16436, U.S. Pat. No.7,446,175, and EP 1313769.

In some embodiments, the MBM is administered in combination with a CD32Binhibitor. In some embodiments, the CD32B inhibitor is an anti-CD32Bantibody molecule. Exemplary anti-CD32B antibody molecules are disclosedin U.S. Pat. No. 8,187,593, 8,778,339, 8,802,089, US20060073142,US20170198040, and US20130251706.

In some embodiments, the MBM is administered in combination with one ofthe compounds listed in Table 18.

TABLE 18 Compound Generic Patents/Patent Desig- Name Application nationTradename Compound Structure Publications A1 Sotrastaurin

EP 1682103 US 2007/142401 WO 2005/039549 A2 Nilotinib HCl monohydrateTASIGNA ®

WO 2004/005281 U.S. Pat. No. 7,169,791 A3

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In some embodiments, a MBM is administered in combination with one ormore of a CAR-T therapy, NIZ985, a GITR agonist such as GWN323, PTK787,MBG453, mAb12425, CLR457, BGT226, BYL719, AMN107, ABL001, IDH305/LQS305,LJM716, MCS110, WNT974/LGK974, BLZ945, NIR178, QBM076, MBG453,CGS-20267, LHS534, LKG960, LDM099/SHP099, TN0155, LCL161, MAP855/LQN716,RAD001, LEJ511, LDK378, LOU064, LSZ102, LEQ506, RAF265/CHIR265,canakinumab, gevokizumab, Anakinra, Rilonacept, CGS-20267, PSC833,GGP-57148B, CGM097, HDM201, LBH589, PKC412, LHC165, MAK683, INC280,INC424, LJE704, LAG525, and NIS793.

In some embodiments, the MBM is administered in combination with astandard treatment.

Standard treatment for multiple myeloma and associated diseases includeschemotherapy, stem cell transplant (autologous or allogeneic), radiationtherapy, and other drug therapies. Frequently used anti-myeloma drugsinclude alkylating agents (e.g., bendamustine, cyclophosphamide andmelphalan), proteasome inhibitors (e.g., bortezomib), corticosteroids(e.g., dexamethasone and prednisone), and immunomodulators (e.g.,thalidomide and lenalidomide or Revlimid®), or any combination thereof.Biphosphonate drugs are also frequently administered in combination withthe standard anti-MM treatments to prevent bone loss. Patients olderthan 65-70 years of age are unlikely candidates for stem celltransplant. In some cases, double-autologous stem cell transplants areoptions for patients less than 60 years of age with suboptimal responseto the first transplant. The compositions and methods of the presentdisclosure can be administered in combination with any one of thecurrently prescribed treatments for multiple myeloma.

Hodgkin's lymphoma is commonly treated with radiation therapy,chemotherapy, or hematopoietic stem cell transplantation. The mostcommon therapy for non-Hodgkin's lymphoma is R-CHOP, which consists offour different chemotherapies (cyclophosphamide, doxorubicin,vincristine, and prenisolone) and rituximab (Rituxan®). Other therapiescommonly used to treat NHL include other chemotherapeutic agents,radiation therapy, stem cell transplantation (autologous or allogeneicbone marrow transplantation), or biological therapy, such asimmunotherapy. Other examples of biological therapeutic agents include,but are not limited to, rituximab (Rituxan®), tositumomab (Bexxar®),epratuzumab (LymphoCide®), and alemtuzumab (MabCampath®). Thecompositions and methods of the present disclosure can be administeredin combination with any one of the currently prescribed treatments forHodgkin's lymphoma or non-Hodgkin's lymphoma.

Standard treatment for WM consists of chemotherapy, specifically withrituximab (Rituxan®). Other chemotherapeutic drugs can be used incombination, such as chlorambucil (Leukeran®), cyclophosphamide(Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), vincristine,and/or thalidomide. Corticosteriods, such as prednisone, can also beadministered in combination with the chemotherapy. Plasmapheresis, orplasma exchange, is commonly used throughout treatment of the patient toalleviate some symptoms by removing the paraprotein from the blood. Insome cases, stem cell transplantation is an option for some patients.

MBMs having an ABM2 that binds to CD3 can be administered in combinationwith an agent which reduces or ameliorates a side effect associated withthe administration of a MBM that binds to CD3. Side effects associatedwith the administration of CD3 binders include, but are not limited to,cytokine release syndrome (“CRS”) and hemophagocytic lymphohistiocytosis(HLH), also termed Macrophage Activation Syndrome (MAS). Symptoms of CRScan include high fevers, nausea, transient hypotension, hypoxia, and thelike. CRS can include clinical constitutional signs and symptoms such asfever, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, andheadache. CRS can include clinical skin signs and symptoms such as rash.CRS can include clinical gastrointestinal signs and symptoms such asnausea, vomiting and diarrhea. CRS can include clinical respiratorysigns and symptoms such as tachypnea and hypoxemia. CRS can includeclinical cardiovascular signs and symptoms such as tachycardia, widenedpulse pressure, hypotension, increased cardiac output (early) andpotentially diminished cardiac output (late). CRS can include clinicalcoagulation signs and symptoms such as elevated d-dimer,hypofibrinogenemia with or without bleeding. CRS can include clinicalrenal signs and symptoms such as azotemia. CRS can include clinicalhepatic signs and symptoms such as transaminitis and hyperbilirubinemia.CRS can include clinical neurologic signs and symptoms such as headache,mental status changes, confusion, delirium, word finding difficulty orfrank aphasia, hallucinations, tremor, dymetria, altered gait, andseizures.

Accordingly, the methods described herein can comprise administering aMBM having an ABM2 that binds to CD3 to a subject and furtheradministering one or more agents to manage elevated levels of a solublefactor resulting from treatment with the MBM. In one embodiment, thesoluble factor elevated in the subject is one or more of IFN-γ, TNFα,IL-2 and IL-6. In an embodiment, the factor elevated in the subject isone or more of IL-1, GM-CSF, IL-10, IL-8, IL-5 and fraktalkine.Therefore, an agent administered to treat this side effect can be anagent that neutralizes one or more of these soluble factors. In oneembodiment, the agent that neutralizes one or more of these solubleforms is an antibody or antigen binding fragment thereof. Examples ofsuch agents include, but are not limited to a steroid (e.g.,corticosteroid), an inhibitor of TNFα, and inhibitor of IL-1R, and aninhibitor of IL-6. An example of a TNFα inhibitor is an anti-TNFαantibody molecule such as, infliximab, adalimumab, certolizumab pegol,and golimumab. Another example of a TNFα inhibitor is a fusion proteinsuch as entanercept. Small molecule inhibitor of TNFα include, but arenot limited to, xanthine derivatives (e.g. pentoxifylline) andbupropion. An example of an IL-6 inhibitor is an anti-IL-6 antibodymolecule such as tocilizumab (toc), sarilumab, elsilimomab, ONTO 328,ALD518/BMS-945429, ONTO 136, CPSI-2364, CDP6038, VX₃₀, AR^(G) X-109,FE301, and FM101. In one embodiment, the anti-IL-6 antibody molecule istocilizumab. An example of an IL-1R based inhibitor is anakinra.

In some embodiment, the subject is administered a corticosteroid, suchas, e.g., methylprednisolone, hydrocortisone, among others. In someembodiments, the subject is administered a corticosteroid, e.g.,methylprednisolone, hydrocortisone, in combination with Benadryl andTylenol prior to the administration of a MBM that binds CD3 to mitigatethe CRS risk.

In some embodiments, the subject is administered a vasopressor, such as,e.g., norepinephrine, dopamine, phenylephrine, epinephrine, vasopressin,or any combination thereof.

In an embodiment, the subject can be administered an antipyretic agent.In an embodiment, the subject can be administered an analgesic agent.

8. EXAMPLES 8.1. Example 1 Production and Characterization of Anti-BCMAAntibodies

Anti-BCMA antibodies that are cross-reactive with both human andcynomolgus BCMA were identified using phage display. Affinity maturationof a selected antibody, designated R1F2 in Table 11, was performed toproduce antibodies having increased affinity for BCMA. Severaladditional anti-BCMA antibodies derived from the parental R1F2 antibodywere obtained. These antibodies are designated as “AB1/AB2 Family”binders in Table 11. Another antibody separately identified using phagedisplay, designated PI-61 in Table 11, was also subjected to affinitymaturation to produce clones having increased affinity for BCMA. Severaladditional anti-BCMA antibodies derived from the parental PI-61 antibodywere obtained. These antibodies are designated as “AB3 Family” bindersin Table 11.

Anti-BCMA x anti-CD3 bispecifc antibodies having VH and VL sequences ofAB1, AB2, and AB3 were produced. The bispecific antibodies were found tobe active in in vitro RTCC assays with BCMA+multiple myeloma cell linesand found to have anti-tumor activity in a KMS11-Luc multiple myelomaorthotopic tumor model in NSG mice.

8.2. Example 2 Production and Characterization of TBMs Binding BCMA, aComponent of a TCR Complex, and CD2

TBMs having a BCMA ABM comprising VH and VL sequences of AB3, a TCR ABM,and a CD2 ABM were produced in a knob-into-hole (KIH) format andcharacterized. The TBMs of this Example are shown schematically in FIGS.2A-2B. Each TBM of this Example comprises a first half antibody (shownschematically as the left half of each construct shown in FIGS. 2A-2B)and a second half antibody (shown schematically as the right half ofeach construct shown in FIGS. 2A-2B). Without being bound by theory, itis believed that combining CD2 and TCR complex-engagement in a TBM canstimulate both a primary signaling pathway that promotes T-cell mediatedlysis of tumor cells (by clustering TCRs, for example) and a second co-stimulatory pathway to induce T-cell proliferation and potentiallyovercome anergy.

8.2.1. Materials and Methods

8.2.1.1. Plasmids Encoding TBMs

Plasmids encoding proteins for two TBMs targeting BCMA, a component of aTCR complex and CD2 were synthesized.

For the first TBM (shown schematically in FIG. 2A), a plasmid encoding acodon optimized anti-BCMA heavy chain was synthesized as a fusioncomprising (in the N-terminal to C-terminal direction) (i) the AB3 VHdomain fused to a constant hIgG1 CH1 domain (ii) a linker, (iii) ananti-TCR scFv corresponding to BMA031, (iv) a second linker, and (v) ahIgG1 Fc region containing T366S, L368A, and Y407V mutations for a holeto facilitate heterodimerization of the TBM as well as silencingmutations. A plasmid encoding a light chain was synthesized as a fusioncomprising (in the N-terminal to C-terminal direction) the AB3 VL domainand the constant human lambda sequence. A plasmid encoding the secondhalf antibody was synthesized as a fusion comprising (in the N-terminalto C-terminal direction) (i) the IgV domain of CD58 (CD58-6), (ii) alinker, and (iii) a constant hIgG1 domain containing a T366W mutationfor the knob to facilitate heterodimerization of the TBM as well assilencing mutations.

For the second TBM (shown schematically in FIG. 2B), a plasmid encodinga codon optimized anti-BCMA heavy chain was synthesized as a fusioncomprising (in the N-terminal to C-terminal direction) (i) the AB3 VHdomain fused to a constant hIgG1 CH1 domain (ii) a linker, (iii) the IgVdomain of CD58 (CD58-6), (iv) a second linker, and (v) a hIgG1 Fc regioncontaining T366S, L368A, and Y407V mutations for a hole to facilitateheterodimerization of the TBM as well as silencing mutations. A plasmidencoding a light chain was synthesized as a fusion comprising (in theN-terminal to C-terminal direction) the AB3 VL domain and the constanthuman lambda sequence. A plasmid encoding the second half antibody wassynthesized as a fusion comprising (in the N-terminal to C-terminaldirection) (i) an anti-TCR scFv corresponding to BMA031, (ii) a linker,and (iii) a constant hIgG1 domain containing a T366W mutation for theknob to facilitate heterodimerization of the TBM as well as silencingmutations.

Architectural antibody controls were also produced to allow assessmentof the impact of geometry of the anti-BCMA and anti-CD3 ABMs onfunctional activity. A construct corresponding to AB3_TCR-CD58 in whichthe CD2 ABM was replaced with a Vhh against hen egg lysozyme(AB3_TCR-HEL) was produced. A one arm antibody (OAA) corresponding toAB3_TCR-CD58, but having no CD2 ABM, and the corresponding bispecificantibody having the BCMA ABM and CD3 ABMs on separate half antibodies(BSP), were also produced.

Amino acid sequences for components of the TBMs are shown in Table 19-A(without Fc sequences) and Table 19-B (with Fc sequences).

TABLE 19-A TBM amino acid sequences Construct Chain SEQ Name DescriptionAmino Acid Sequence ID NO: AB3_TCR- First HalfQVQLVESGGGWVQPGRSLRLSCAASGFTVSSYGMHWWRQA 556 CD58 AntibodyPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLYLQ HeavyMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVS ChainSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS (FcWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI sequenceCNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLQQSG not shown)PELVKPGASVKMSCKASGYKFTSYVMHWVKQKPGQGLEWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSATSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKGGGGS First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQH 557 AntibodyPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQAE Light ChainDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS Second HalfSQQIYGVYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSE 558 AntibodyFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDT (Fc MKFFLYVLESGGGGS sequencenot shown) AB3_CD58 First Half QVQLVESGGGWQPGRSLRLSCAASGFTVSSYGMHWVRQA559 TCR Antibody PGKGLEWWAVISYTGSNKYYADSVKGRFTISRDNSKNTLYLQ HeavyMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVS ChainSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS (FcWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYI sequenceCNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSSQQIYGWY not shown)GNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTMKFFLYVLE SGGGGS First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQH 557 AntibodyPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQAE Light ChainDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS Second HalfEVQLQQSGPELVKPGASVKMSCKASGYKFTSYVMHWVKQK 560 AntibodyPGQGLEWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYME (FcLSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSAGG sequenceGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMT not shown)CSATSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKL ELKGGGGS AB3_TCR- First HalfQVQLVESGGGWQPGRSLRLSCAASGFTVSSYGMHWVRQA 556 HEL AntibodyPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLYLQ HeavyMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVS ChainSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS (FcWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI sequenceCNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLQQSG not shown)PELVKPGASVKMSCKASGYKFTSYVMHWVKQKPGQGLEWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSATSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKGGGGS First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQH 557 AntibodyPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQAE Light ChainDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS Second HalfDVQLQASGGGSVQAGGSLRLSCAASGYTIGPYCMGWFRQA 561 AntibodyPGKEREGVAAINMGGGITYYADSVKGRFTISQDNAKNTVYLL (FcMNSLEPEDTAIYYCAADSTIYASYYECGHGLSTGGYGYDSW sequence GQGTQVTVSSGGGGSnot shown)

TABLE 19-B TBM amino acid sequences Construct Chain Amino Acid SequenceSEQ Name Description ID NO: AB3_TCR- First HalfQVQLVESGGGWVQPGRSLRLSCAASGFTVSSYGMHWWRQA 862 CD58 AntibodyPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLYLQ HeavyMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVS ChainSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS (includes FcWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI sequence)CNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLQQSGPELVKPGASVKMSCKASGYKFTSYVMHWVKQKPGQGLEWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSATSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGKFirst Half QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQH 557 AntibodyPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQAE Light ChainDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS Second HalfSQQIYGWYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSE 863 AntibodyFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDT (includes FcMKFFLYVLESGGGGSDKTHTCPPCPAPELLGGPSVFLFPPK sequence)PKDTLMISRTPEVTOWWVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWL.NGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPOREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK AB3_CD58 First HalfQVQLVESGGGWQPGRSLRLSCAASGFTVSSYGMHWWRQA 864 TCR AntibodyPGKGLEWWAVISYTGSNKYYADSVKGRFTISRONSKNTLYLQ HeavyMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVS ChainSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS (includes FcWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYI sequence)CNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSSQQIYGVYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTMKFFLYVLESGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEWCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGKFirst Half QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQH 557 AntibodyPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQAE Light ChainDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS Second HalfEVQLQQSGPELVKPGASVKMSCKASGYKFTSYVMHWVKQK 865 AntibodyPGQGLEWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYME (includes FcLSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSAGG sequence)GGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSATSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNRYTQKSLSLSPGKAB3_TCR- First Half QVQLVESGGGWVQPGRSLRLSCAASGFTVSSYGMHWWRQA 862 HELAntibody PGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLYLQ HeavyMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLVTVS ChainSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS (includes FcWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI sequence)CNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLQQSGPELVKPGASVKMSCKASGYKFTSYVMHWVKQKPGQGLEWIGYINPYNDVTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVHYCARGSYYDYDGFVYWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSATSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGKFirst Half QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQH 557 AntibodyPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQAE Light ChainDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS Second HalfDVQLQASGGGSVQAGGSLRLSCAASGYTIGPYCMGWFRQA 866 AntibodyPGKEREGVAAINMGGGITYYADSVKGRFTISQDNAKNTVYLL (includes FcMNSLEPEDTAIYYCAADSTIYASYYECGHGLSTGGYGYDSW sequence)GQGTQVTVSSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK

8.2.1.2. Expression and Purification

TBMs were expressed transiently by co-transfection of the respectivechains in HEK293 cells. Briefly, transfection of the cells with theheavy and light chain plasmids was performed using PEI as transfectionreagent with a final DNA:PEI ratio of 1:3. 1 mg of plasmid per liter ofculture was used for transfection of cultures having 2.0 millioncells/mL of serum media. After 5 days of expression, TBMs were harvestedby clarification of the media via centrifugation and filtration.Purification was performed via anti-CH1 affinity batch binding(CaptureSelect IgG-CH1 Affinity Matrix, Thermo-Fisher Scientific,Waltham, Mass., USA) or Protein A (rProteinA Sepharose, Fast flow, GEHealthcare, Uppsala, Sweden) batch binding using 1m1 resin, 100 mLsupernatant. The protein was allowed to bind for a minimum of 2 hourswith gentle mixing, and the supernatant loaded onto a gravity filtrationcolumn. The resin was washed with 20-50 CV of PBS. TBMs were eluted with20 CV of 50 mM citrate, 90 mM NaCI pH 3.2. 50mM sucrose. The eluted TBMfractions were adjusted to pH 5.5 with 1 M sodium citrate 50mM sucrose.Preparative size exclusion chromatography was performed using Hi Load16/60 Superdex 200 grade column (GE Healthcare Life Sciences, Uppsala,Sweden) as a final polishing step when aggregates were present. Toconfirm that the identity of the proteins of the TBMs expressed matchedthe predicted masses for the primary amino acid sequences, proteins wereanalyzed by high-performance liquid chromatography coupled to massspectrometry.

Bispecific constructs were similarly expressed and purified.

8.2.1.3. RTCC Assay

Trispecific and bispecific constructs were evaluated for their potentialto induce T cell- mediated apoptosis in tumor target cells. Briefly,huBCMA-expressing KMS11 target cells were engineered to overexpressfirefly luciferase. Cells were harvested and resuspendend in RPMI medium(Invitrogen # 11875-093) with 10% FBS. 2,500 target cells per well wereplated in a flat-bottom 384-well plate. Human pan T effector cells wereisolated via negative selection (Stemcell Technologies #17951) fromcryopreserved PBMCs that were separated from a leukopak (Hemacare#PB001F-1) by Ficoll density gradient centrifugation. Purified T cellswere then added to the plate to obtain a final E:T ratio of 5:1, 3:1,1:1, 1:3 or 1:5. Co-cultured cells were incubated with a serial dilutionof all constructs and controls. For normalization, average maximumluminescence refers to target cells co-incubated with effector cells,but without any test construct. After an incubation of 48 hours at 37°C., 5% CO₂, OneGlo luciferase substrate (Promega #E6120) was added tothe plate. Luminescence was measured on an Envision plate reader after a10 minute incubation. Percent specific lysis was calculated using thefollowing equation:

Specific lysis(%)=(1−(sample luminescence/average maximumluminescence))*100

8.2.1.4. Cytokine Release Assay

Trispecific constructs were analyzed for their ability to induce Tcell-mediated de novo secretion of cytokines in the presence of tumortarget cells. Briefly, huBCMA-expressing KMS11 target cells wereengineered to overexpress firefly luciferase. Cells were harvested andresuspendend in RPMI medium (Invitrogen #11875-093) with 10% FBS. 10,000target cells per well were plated in a flat-bottom 96-well plate. Humanpan T effector cells were isolated via negative selection (StemcellTechnologies #17951) from cryopreserved PBMCs that were separated from aleukopak (Hemacare #PB001F-1) by Ficoll density gradient centrifugation.Purified T cells were then added to the plate to obtain a final E:Tratio of either 5:1, 1:1, or 1:5. Co-cultured cells were incubated witha serial dilution of all constructs and controls. After an incubation of24 hours at 37° C., 5% CO₂ the supernatants were harvested bycentrifugation at 300×g for 5 min for subsequent analysis. A multiplexedELISA was performed according to the manufacturer's instructions using aV-PLEX Proinflammatory Panel 1 Kit (MesoScale Discovery #K15049D).

8.2.2. Results

RTCC data is shown in FIGS. 3A-E and cytokine levels are shown in FIGS.4A-C. Each of the constructs was active in the RTCC assay.

8.3. Example 3 Production and Characterization of TBMs Binding BCMA,CD3, and CD2

TBMs targeting BCMA, CD3, and CD2 in a knob-into-hole (KIH) format areproduced and characterized according to the Materials and Methodsdescribed in Example 2, except that the TCR ABMs of the constructs ofExample 2 are replaced with sequences for CD3 binders as shown in Table20-A (without Fc sequences) and Table 20-B (with Fc sequences).

TABLE 20-A TBM amino acid sequences Chain SEQ TBM Name DescriptionAmino Acid Sequence ID NO: BCMA_AB3_ First HalfQVQLVESGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQ 562 CD3- AntibodyAPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLY 16nM- HeavyLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLV CD58 ChainTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV (FcTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT sequenceQTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLV not shown)ESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAWTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLW VFGGGTKLTVLGGGGS First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ 557 AntibodyHPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQ Light ChainAEDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS Second HalfSQQIYGWYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSE 558 AntibodyFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITD (Fc TMKFFLYVLESGGGGS sequencenot shown) BCMA_AB3_ First Half QVQLVESGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQ559 CD58 Antibody APGKGLEWWAVISYTGSNKYYADSVKGRFTISRONSKNTLY CD3-16nMHeavy LQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLV ChainTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV (FcTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGT sequenceQTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSSQQIY not shown)GWYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTMKF FLYVLESGGGGS First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ 557 AntibodyHPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQ Light ChainAEDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS Second HalfEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQA 563 AntibodySGKGLEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTL (FcYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTL sequenceVTVSSGGGGSGGGGSGGGGSGGGGSQAVVTQEPSLTVS not shown)PGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALW YSNLWVFGGGTKLTVLGGGGS BCMA_AB3_First Half QVQLVESGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQ 562 CD3- AntibodyAPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLY 16nM HEL HeavyLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLV ChainTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV (FcTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT sequenceQTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLV not shown)ESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAWTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLW VFGGGTKLTVLGGGGS First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ 557 AntibodyHPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQ Light ChainAEDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS Second HalfDVQLQASGGGSVQAGGSLRLSCAASGYTIGPYCMGWFRQ 561 AntibodyAPGKEREGVAAINMGGGITYYADSVKGRFTISQDNAKNTVY (FcLLMNSLEPEDTAIYYCAADSTIYASYYECGHGLSTGGYGYD sequence SWGQGTQVTVSSGGGGSnot shown)

TABLE 20-B TBM amino acid sequences Chain Amino Acid Sequence SEQTBM Name Description ID NO: BCMA_AB3_ First HalfQVQLVESGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQ 867 CD3- AntibodyAPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLY 16nM- HeavyLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLV CD58 ChainTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV (includes FcTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT sequence)QTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAWTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGGGTKLTVLGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ 557 AntibodyHPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQ Light ChainAEDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS Second HalfSQQNYGWYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSE 863 AntibodyFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITD (includes FcTMKFFLYVLESGGGGSDKTHTCPPCPAPELLGGPSVFLFPP sequence)KPKDTLMISRTPEVTCVWVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK BCMA_AB3_ First HalfQVQLVESGGGWQPGRSLRLSCAASGFTVSSYGMHWWRQ 864 CD58 AntibodyAPGKGLEWWAVISYTGSNKYYADSVKGRFTISRDNSKNTLY CD3-16nM HeavyLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLV ChainTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV (includes FcTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGT sequence)QTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSSQQIYGWYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTMKFFLYVLESGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ 557 AntibodyHPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQ Light ChainAEDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS Second HalfEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQA 868 AntibodySGKGLEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTL (includes FcYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTL sequence)VTVSSGGGGSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGGGTKLTVLGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSL SLSPGK BCMA_AB3_ First HalfQVQLVESGGGVVQPGRSLRLSCAASGFTVSSYGMHWVRQ 867 CD3- AntibodyAPGKGLEWVAVISYTGSNKYYADSVKGRFTISRDNSKNTLY 16nM HEL HeavyLQMNSLRAEDTAVYYCGGSGYALHDDYYGLDVWGQGTLV ChainTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV (includes FcTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT sequence)QTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYATYYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSQAWTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGGGTKLTVLGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK First HalfQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQ 557 AntibodyHPGKAPKLMIYDVSNRLRGVSNRFSGSKSGNTASLTISGLQ Light ChainAEDEADYYCSSYTSSSALYVFGSGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS Second HalfDVQLQASGGGSVQAGGSLRLSCAASGYTIGPYCMGWFRQ 866 AntibodyAPGKEREGVAAINMGGGITYYADSVKGRFTISQDNAKNTVY (includes FcLLMNSLEPEDTAIYYCAADSTIYASYYECGHGLSTGGYGYD sequence)SWGQGTQVTVSSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSP GK

RTCC and cytokine release assays are performed as in Example 2. Thetrispecific constructs are active in the RTCC assay.

8.4. Example 4 Engineering CD58 for Improved Stability

8.4.1. Background

Human CD58 contains a signal peptide of 29 amino acids and two Ig-likedomains. The most N-terminal Ig-like domain, referred to as domain 1, isof V-type, similar to a variable region of an antibody, and the seconddomain, named domain 2, is of C-type, is similar to a constant regionsof an antibody. A schematic overview of the CD58 domain structure isshown in FIG. 5 .

As illustrated in Example 2, domain 1 of CD58, which interacts with CD2,can be used in lieu of an anti-CD2 antibody binding fragment inmultispecific binding molecules. However, CD58 exhibits lower stabilitythan immunoglobulins.

In order to improve stability of human CD58 domain 1, the protein wasengineered to include a pair of cysteine that form a disulfide bridgeupon expression to stabilize the molecule.

Four different pairs of amino acids were engineered to be replaced bycysteines: (1) V45 and M105, (2) V45 and M114, (3) V54 and G88 and (4)W56 and L90.

8.4.2. Materials and Methods

8.4.2.1. Recombinant Expression

To assess the binding and biophysical characteristics, the CD58disulfide variants were transiently produced and purified from HEK293cells along with the CD2 extracellular domain. All plasmids were codonoptimized for mammalian expression. Human and cyno CD2 constructs wereproduced with a C-terminal Avi-Tag and a N terminal 8xhis tag (SEQ IDNO: 564) followed by a EVNLYFQS sequence (SEQ ID NO: 565) for cleavageof the histag after purification. CD2 constructs were site selectivelybiotinylated during expression via co-transfection of a plasmid encodingthe BirA enzyme. CD58 was expressed with a C-terminal 8× his tag (SEQ IDNO: 564). Transient expression and purification in HEK293F cells wasperformed with standard methodology. The sequences are shown in Table21.

TABLE 21 SEQ ID Protein Name AA Sequence NO: Human CD2SKEITNALETWGALGQDINLDIPSFQMSDDIDDIKWEKTS 566DKKKIAQFRKEKETFKEKDTYKLFKNGTLKIKHLKTDDQDIYKVSIYDTKGKNVLEKIFDLKIQERVSKPKISWTCINTTLTCEVMNGTDPELNLYQDGKHLKLSQRVITHKWTTSLSAKFKCTAGNKVSKESSVEPVSCPEKGLDGGGGSGLNDI FEAQKIEWHE Cyno CD2SKEIRNALETWGALGQDIDLDIPSFQMSDDIDDIRWEKT 567SDKKKIAQFRKEKETFEEKDAYKLFKNGTLKIKHLKIHDQDSYKVSIYDTKGKNVLEKTFDLKIQERVSEPKISWTCINTTLTCEVMNGTDPELNLYQDGKHVKLSQRVITHKWTTSLSAKFKCTAGNKVSKESRMETVSCPEKGLDGGGGSGLN DIFEAQKIEWHE CD58 Full ECDSQQIYGVVYGNVTFHVPSNVPLKEVLWKKQKDKVAELE 568NSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTMKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEHYNSHRGLIMYSWDCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIPSSGHSRHRGGGGSHHH HHHHH CD58_IgVSQQIYGWYGNVTFHVPSNVPLKEVLWKKQKDKVAELE 569NSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEME SPNITDTMKFFLYVLESGGGGSHHHHHHHHIgV SQQIYGWYGNVTFHCPSNVPLKEVLWKKQKDKVAELE 570 V45C_M105CNSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYECE SPNITDTMKFFLYVLESGGGGSHHHHHHHHIgV SQQIYGVVYGNVTFHVPSNVPLKECLWKKQKDKVAELE 571 V54C_G88CNSEFRAFSSFKNRVYLDTVSCSLTIYNLTSSDEDEYEME SPNITDTMKFFLYVLESGGGGSHHHHHHHHIgV SQQIYGVVYGNVTFHCPSNVPLKEVLWKKQKDKVAELE 572 V45C_M114CNSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEME SPNITDTCKFFLYVLESGGGGSHHHHHHHH

For expression, transfection was performed using PEI as transfectionreagent. For small scale (<5L) transfections, cells were grown in shakeflasks on an orbital shaker (100 rpm) in a humidified incubator (85%) at8% CO2). Transfection was done with a ratio of 1 DNA: 3 PEI. 1mg/Lculture of plasmid was used for transfection at 2.0 million cells/mL inExpi293 medium. After 5 days of expression, the culture was centrifugedand filtrated. Purification was performed via Nickel-NTA batch bindingusing 1 ml resin, 100 mL supernatant. The protein was allowed to bindfor a minimum of 2 hours with gentle mixing, and the mixture was loadedonto a gravity filtration column. The resin was washed with 30 CV ofPBS. Proteins were eluted with imidazole. The eluted protein wasconcentrated and finally purified via a preparative size exclusionchromatography (Hi Load 16/60 Superdex 75 grade column, GE HealthcareLife Sciences, Uppsala, Sweden). To confirm that the identity of theproteins expressed matched the predicted masses for the primary aminoacid sequences, proteins were analyzed by high-performance liquidchromatography coupled to mass spectrometry.

8.4.2.2. Stability

Disulfide stabilized variants were assessed for improved thermalstability using both differential scanning calorimetry (DSC) anddifferential scanning fluorimetry (DSF) using standard techniques. ForDSF, 1-3 ug of each construct was add to lx Sypro Orange (Thermo-Fisher)in 25 ul total volume in 96-well PCR plate. Using a Bio-Rad CFX₉₆ RT-PCRsystem equipped with C1000 Thermal Cycler, the temperature was increasedfrom 25° C. to 95° C. at 0.5° C./minute and the fluorescence monitored.The manufacturer-supplied software was used to determine Tm.

For DSC, all samples were dialyzed into HEPES-buffered saline (HBS) anddiluted to final concentration of 0.5 mg/mL. Tm and Tonset weredetermined using a MicroCal VP-Capillary DSC system (Malvern) byincreasing temperature from 25° C. to 100° C. at 1° C./minute with afiltering period of 2 seconds and a mid-gain setting.

8.4.2.3. Binding Affinity

To ensure the binding affinity remained uncompromised by the additionalof the stabilizing disulfide variance, isothermal calorimetry (ITC) wasperformed on the resulting recombinant CD58 proteins to determine theirapparent KD and binding stoicheometry (n) to recombinant human CD2.

Briefly, recombinant human CD2 and recombinant human CD58 variants weredialyzed into HEPES-buffered saline (HBS). CD2 was diluted to finalconcentration of 100 μM, CD58 variants were diluted to 10 μM. CD2 wastitrated into 10 μM of CD58 variants via multiple injections and ΔH(kcal/mole) determined using a MicroCal VP-ITC isothermal titrationcalorimeter (Malvern). Titrations of CD2 into HBS were used as areference and KD and n determined from the resulting data.

8.4.3. Results

Results for both DSF and DSC measurements for the constructs are shownin Table 22 below.

TABLE 22 By Differential Scanning By Differential Scanning Fluorimetry(DSF) Calorimetry (DSC) CD58 variant Tm (° C.) Tmonset (° C.) Tm (° C.)CD58 Full ECD 59.5 48.8 65.0 CD58_IgV 48.5 46.3 60.9 IgV V45C_M105C 48.543.9 66.8 IgV V54C_G88C 76.5 66.7 80.9 IgV V45C_M114C 63.5 49.6 72.5

Results of the affinity studies are shown in Table 23 below. Addition ofstabilizing disulfide had no detrimental impact on the affinity or thebinding stoicheometry.

TABLE 23 CD58 variant KD (uM) n CD58 Full ECD 0.57 (±0.05) 0.92 (±0.01)CD58_IgV 0.61 (±0.07) 0.96 (±0.01) IgV V45C_M105C 0.88 (±0.06) 0.97(±0.01) IgV V54C_G88C 0.60 (±0.06) 0.83 (±.0.01) IgV V45C_M114C 0.38(±0.03) 0.88 (±.0.01)

9. SPECIFIC EMBODIMENTS, CITATION OF REFERENCES

While various specific embodiments have been illustrated and described,it will be appreciated that various changes can be made withoutdeparting from the spirit and scope of the disclosure(s). The presentdisclosure is exemplified by the numbered embodiments set forth below.

1. A multispecific binding molecule (MBM), comprising:

-   -   (a) an antigen-binding module 1 (ABM1) that binds specifically        to human BCMA and comprises CDR-L1, CDR-L2 and CDR-L3 sequences        set forth in Table 11A-1, Table 11B-1, Table 11C-1, Table 11D-1,        Table 11E-1, Table 11F-1, Table 11G-1, Table 11H-1, Table 11I-1,        Table 11J-1, Table 11K-1(a), Table 11K-1(b), Table 11L-1, Table        11M-1, Table 11N-1(a), or Table 11N-1(b), and the corresponding        CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table 11A-2,        Table 11B-2, Table 11C-2, Table 11D-2, Table 11E-2, Table 11F-2,        Table 11G-2, Table 11H-2, Table 11I-2, Table 11J-2, Table 11K-2,        Table 11K-2, Table 11L-2, Table 11M-2, Table 11N-2, or Table        11N-2, respectively;    -   (b) an antigen-binding module 2 (ABM2) that binds specifically        to a component of a human T-cell receptor (TCR) complex; and    -   (c) an antigen-binding module 3 (ABM3) that binds specifically        to human CD2 or a human tumor-associated antigen (TAA).

2. The MBM of embodiment 1, wherein ABM1 comprises CDR-L1, CDR-L2 andCDR-L3 sequences set forth in Table 11A-1, Table 11B-1, Table 11C-1,Table 11D-1, Table 11E-1, Table 11F-1, Table 11G-1, Table 11H-1, Table11I-1, Table 11J-1, Table 11K-1(a), Table 11L-1, Table 11M-1, or Table11N-1(a), and the corresponding CDR-H1, CDR-H2 and CDR-H3 sequence setforth in Table 11A-2, Table 11B-2, Table 11C-2, Table 11D-2, Table11E-2, Table 11F-2, Table 11G-2, Table 11H-2, Table 11I-2, Table 11J-2,Table 11K-2, Table 11L-2, Table 11M-2, or Table 11N-2, respectively.

3. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11A-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11A-2.

4. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11B-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11B-2.

5. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11C-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11C-2.

6. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11D-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11D-2.

7. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11E-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11E-2.

8. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11F-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11F-2.

9. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11G-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11G-2.

10. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11H-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11H-2.

11. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11I-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11I-2.

12. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11J-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11J-2.

13. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11K-1(a) and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11K-2.

14. The MBM of embodiment 1, wherein ABM1 comprises CDR-L1, CDR-L2 andCDR-L3 sequences set forth in Table 11K-1(b) and the correspondingCDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table 11K-2.

15. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11L-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11L-2.

16. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11M-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11M-2.

17. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11N-1(a) and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11N-2.

18. The MBM of embodiment 1, wherein ABM1 comprises CDR-L1, CDR-L2 andCDR-L3 sequences set forth in Table 11N-1(b) and the correspondingCDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table 11N-2.

19. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C1.

20. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C2.

21. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C3.

22. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C4.

23. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C5.

24. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C6.

25. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C7.

26. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C8.

27. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C9.

28. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C10.

29. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C11.

30. The MBM of embodiment 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C12.

31. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C13.

32. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C14.

33. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C15.

34. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C16.

35. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C17.

36. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C18.

37. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C19.

38. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C20.

39. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C21.

40. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C22.

41. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C23.

42. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C24.

43. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C25.

44. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C26.

45. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C27.

46. The MBM of embodiment 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C28.

47. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of AB1.

48. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of AB2.

49. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of R1F2.

50. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF03.

51. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF04.

52. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF05.

53. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF06.

54. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF07.

55. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF08.

56. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF09.

57. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF12.

58. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF13.

59. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF14.

60. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF15.

61. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF16.

62. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF17.

63. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF18.

64. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF19.

65. The MBM of any one of embodiments 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF20.

66. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of AB3.

67. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of P1-61.

68. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-22.

69. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-88.

70. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-36.

71. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-34.

72. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-68.

73. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-18.

74. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-47.

75. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-20.

76. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-80.

77. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH₂/L2-83.

78. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-1.

79. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-2.

80. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-3.

81. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-4.

82. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-5.

83. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-6.

84. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-7.

85. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-8.

86. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-9.

87. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-10.

88. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-11.

89. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-12.

90. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-13.

91. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-14.

92. The MBM of any one of embodiments 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-15.

93. The MBM of embodiment 1 or embodiment 2, wherein ABM1 comprises alight chain variable sequence set forth in Table 11O-1 and thecorresponding heavy chain variable sequence set forth in Table 11O-2.

94. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of AB1.

95. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of AB2.

96. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of AB3.

97. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of R1F2.

98. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF03.

99. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF04.

100. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF05.

101. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF06.

102. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF07.

103. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF08.

104. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF09.

105. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF12.

106. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF13.

107. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF14.

108. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF15.

109. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF16.

110. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF17.

111. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF18.

112. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF19.

113. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PALF20.

114. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of PI-61.

115. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-88.

116. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-36.

117. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-34.

118. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-68.

119. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-18.

120. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-47.

121. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-20.

122. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-80.

123. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those ofH₂/L2-83.

124. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-1.

125. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-2.

126. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-3.

127. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-4.

128. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-5.

129. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-6.

130. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-7.

131. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-8.

132. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-9.

133. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-10.

134. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-11.

135. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-12.

136. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-13.

137. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-14.

138. The MBM of embodiment 93, wherein the light chain variable sequenceand the corresponding heavy chain variable sequence are those of H3-15.

139. The MBM of any one of embodiments 1 to 138, wherein ABM1 is anantibody, an antibody fragment, an scFv, a dsFv, a Fv, a Fab, an scFab,a (Fab′)2, or a single domain antibody (SDAB).

140. The MBM of embodiment 139, wherein ABM1 comprises an antibody or anantigen-binding domain thereof.

141. The MBM of embodiment 139, wherein ABM1 comprises a scFv.

142. The MBM of embodiment 141, wherein the scFv of ABM1 comprises asequence set forth in Table 11P.

143. The MBM of any one of embodiments 1 to 142, wherein ABM2 is anon-immunoglobulin scaffold based ABM.

144. The MBM of embodiment 143, wherein ABM2 is a Kunitz domain, anAdnexin, an Affibody, a DARPin, an Avimer, an Anticalin, a Lipocalin, aCentyrin, a Versabody, a Knottin, an Adnectin, a Pronectin, anAffitin/Nanofitin, an Affilin, an Atrimer/Tetranectin, a bicyclicpeptide, a cys-knot, a Fn3 scaffold, an Obody, a Tn3, an Affimer, BD, anAdhiron, a Duocalin, an Alphabody, an Armadillo Repeat Protein, aRepebody, or a Fynomer

145. The MBM of any one of embodiments 1 to 142, wherein ABM2 is animmunoglobulin scaffold based ABM.

146. The MBM of embodiment 145, wherein ABM2 is an antibody, an antibodyfragment, an scFv, a dsFv, a Fv, a Fab, an scFab, a (Fab′)2, a singledomain antibody (SDAB), a VH or VL domain, or a camelid VHH domain.

147. The MBM of embodiment 146, wherein ABM2 is an antibody or anantigen-binding domain thereof.

148. The MBM of embodiment 146, wherein ABM2 is an scFv.

149. The MBM of embodiment 146, wherein ABM2 is a Fab.

150. The MBM of embodiment 149, wherein ABM2 is a Fab heterodimer.

151. The MBM of any one of embodiments 1 to 150, wherein the componentof the TCR complex is CD3.

152. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-1.

153. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-2.

154. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-3.

155. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-4.

156. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-5.

157. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-6.

158. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof

CD3-7.

159. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-8.

160. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-9.

161. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-10.

162. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-11.

163. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-12.

164. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-13.

165. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-14.

166. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-15.

167. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-16.

168. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-17.

169. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-18.

170. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-19.

171. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-20.

172. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-21.

173. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-22.

174. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-23.

175. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-24.

176. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-25.

177. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-26.

178. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-27.

179. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-28.

180. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-29.

181. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-30.

182. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-31.

183. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-32.

184. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-33.

185. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-34.

186. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-35.

187. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-36.

188. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-37.

189. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-38.

190. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-39.

191. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-40.

192. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-41.

193. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-42.

194. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-43.

195. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-44.

196. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-45.

197. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-46.

198. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-47.

199. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-48.

200. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-49.

201. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-50.

202. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-51.

203. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-52.

204. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-53.

205. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-54.

206. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-55.

207. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-56.

208. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-57.

209. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-58.

210. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-59.

211. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-60.

212. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-61.

213. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-62.

214. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-63.

215. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-64.

216. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-65.

217. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-66.

218. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-67.

219. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-68.

220. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-69.

221. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-70.

222. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-71.

223. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-72.

224. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-73.

225. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-74.

226. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-75.

227. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-76.

228. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-77.

229. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-78.

230. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-79.

231. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-80.

232. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-81.

233. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-82.

234. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-83.

235. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-84.

236. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-85.

237. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-86.

238. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-87.

239. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-88.

240. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-89.

241. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-90.

242. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-91.

243. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-92.

244. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-93.

245. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-94.

246. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-95.

247. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-96.

248. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-97.

249. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-98.

250. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-99.

251. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-100.

252. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-101.

253. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-102.

254. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-103.

255. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-104.

256. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-105.

257. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-106.

258. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-107.

259. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-108.

260. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-109.

261. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-110.

262. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-111.

263. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-112.

264. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-113.

265. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-114.

266. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-115.

267. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-116.

268. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-117.

269. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-118.

270. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-119.

271. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-120.

272. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-121.

273. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-122.

274. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-123.

275. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-124.

276. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-125.

277. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-126.

278. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-127.

279. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-128.

280. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-129.

281. The MBM of embodiment 151, wherein ABM2 comprises the CDR sequencesof CD3-130.

282. The MBM of any one of embodiments 152 to 281, wherein the CDRs aredefined by Kabat numbering, as set forth in Table 12B.

283. The MBM of any one of embodiments 152 to 281, wherein the CDRs aredefined by Chothia numbering, as set forth in Table 12C.

284. MBM of any one of embodiments 152 to 281, wherein the CDRs aredefined by a combination of Kabat and Chothia numbering, as set forth inTable 12D.

285. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-1, as set forth in Table 12A.

286. The of embodiment 151, wherein ABM2 comprises the heavy and lightchain variable sequences of CD3-2, as set forth in Table 12A.

287. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-3, as set forth in Table 12A.

288. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-4, as set forth in Table 12A.

289. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-5, as set forth in Table 12A.

290. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-6, as set forth in Table 12A.

291. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-7, as set forth in Table 12A.

292. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-8, as set forth in Table 12A.

293. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-9, as set forth in Table 12A.

294. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-10, as set forth in Table 12A.

295. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-11, as set forth in Table 12A.

296. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-12, as set forth in Table 12A.

297. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-13, as set forth in Table 12A.

298. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-14, as set forth in Table 12A.

299. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-15, as set forth in Table 12A.

300. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-16, as set forth in Table 12A.

301. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-17, as set forth in Table 12A.

302. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-18, as set forth in Table 12A.

303. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-19, as set forth in Table 12A.

304. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-20, as set forth in Table 12A.

305. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-21, as set forth in Table 12A.

306. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-22, as set forth in Table 12A.

307. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-23, as set forth in Table 12A.

308. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-24, as set forth in Table 12A.

309. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-25, as set forth in Table 12A.

310. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-26, as set forth in Table 12A.

311. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-27, as set forth in Table 12A.

312. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-28, as set forth in Table 12A.

313. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-129, as set forth in Table 12A.

314. The MBM of embodiment 151, wherein ABM2 comprises the heavy andlight chain variable sequences of CD3-130, as set forth in Table 12A.

315. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-12 in Table 12A.

316. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-21 in Table 12A.

317. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-22 in Table 12A.

318. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-23 in Table 12A.

319. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-24 in Table 12A.

320. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-25 in Table 12A.

321. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-26 in Table 12A.

322. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-27 in Table 12A.

323. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-28 in Table 12A.

324. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-129 in Table 12A.

325. The MBM of embodiment 151, wherein ABM2 comprises the amino acidsequence of the scFv designated as CD3-130 in Table 12A.

326. The MBM of embodiment 151, wherein ABM2 comprises a CDR-H1sequence, a CDR-H2 sequence, a CDR-H3 sequence, a CDR-L1 sequence, aCDR-L2 sequence, and a CDR-L3 sequence set forth in Table AA, Table AB,or Table AC.

327. The MBM of embodiment 326, wherein ABM2 comprises a CDR-H1sequence, a CDR-H2 sequence, a CDR-H3 sequence, a CDR-L1 sequence, aCDR-L2 sequence, and a CDR-L3 sequence set forth in Table AA.

328. The MBM of embodiment 327, wherein the amino acid designated X₁ inTable AA is T.

329. The MBM of embodiment 327, wherein the amino acid designated X₁ inTable AA is A.

330. The MBM of any one of embodiments 327 to 329, wherein the aminoacid designated X₂ in Table AA is S.

331. The MBM of any one of embodiments 327 to 329, wherein the aminoacid designated X₂ in Table AA is R.

332. The MBM of any one of embodiments 327 to 331, wherein the aminoacid designated X₃ in Table AA is N.

333. The MBM of any one of embodiments 327 to 331, wherein the aminoacid designated X₃ in Table AA is Y.

334. The MBM of any one of embodiments 327 to 331, wherein the aminoacid designated X₃ in Table AA is Q.

335. The MBM of any one of embodiments 327 to 334, wherein the aminoacid designated X₄ in Table AA is H.

336. The MBM of any one of embodiments 327 to 334, wherein the aminoacid designated X₄ in Table AA is S.

337. The MBM of any one of embodiments 327 to 336, wherein the aminoacid designated X₅ in Table AA is M.

338. The MBM of any one of embodiments 327 to 336, wherein the aminoacid designated X₅ in Table AA is L.

339. The MBM of any one of embodiments 327 to 338, wherein the aminoacid designated X₆ in Table AA is K.

340. The MBM of any one of embodiments 327 to 338, wherein the aminoacid designated X₆ in Table AA is R.

341. The MBM of any one of embodiments 327 to 340, wherein the aminoacid designated X₇ in Table AA is S.

342. The MBM of any one of embodiments 327 to 340, wherein the aminoacid designated X₇ in Table AA is K.

343. The MBM of any one of embodiments 327 to 342, wherein the aminoacid designated X₅₅ in Table AA is F.

344. The MBM of any one of embodiments 327 to 342, wherein the aminoacid designated X₅₅ in Table AA is Y.

345. The MBM of any one of embodiments 327 to 342, wherein the aminoacid designated X₅₅ in Table AA is S.

346. The MBM of any one of embodiments 327 to 345, wherein the aminoacid designated X₈ in Table AA is W.

347. The MBM of any one of embodiments 327 to 345, wherein the aminoacid designated X₈ in Table AA is Y.

348. The MBM of any one of embodiments 327 to 345, wherein the aminoacid designated X₈ in Table AA is S.

349. The MBM of any one of embodiments 327 to 345, wherein the aminoacid designated X₈ in Table AA is T.

350. The MBM of any one of embodiments 327 to 349, wherein the aminoacid designated X₉ in Table AA is W.

351. The MBM of any one of embodiments 327 to 349, wherein the aminoacid designated X₉ in Table AA is Y.

352. The MBM of any one of embodiments 327 to 349, wherein the aminoacid designated X₉ in Table AA is S.

353. The MBM of any one of embodiments 327 to 349, wherein the aminoacid designated X₉ in Table AA is T.

354. The MBM of any one of embodiments 327 to 353, wherein the aminoacid designated X₁₀ in Table AA is H.

355. The MBM of any one of embodiments 327 to 353, wherein the aminoacid designated X₁₀ in Table AA is Y.

356. The MBM of any one of embodiments 327 to 355, wherein the aminoacid designated X₁₁ in Table AA is S.

357. The MBM of any one of embodiments 327 to 355, wherein the aminoacid designated X₁₁ in Table AA is G.

358. The MBM of any one of embodiments 327 to 357, wherein the aminoacid designated X₁₂ in Table AA is I.

359. The MBM of any one of embodiments 327 to 357, wherein the aminoacid designated X₁₂ in Table AA is L.

360. The MBM of any one of embodiments 327 to 359, wherein the aminoacid designated X₁₃ in Table AA is V.

361. The MBM of any one of embodiments 327 to 359, wherein the aminoacid designated X₁₃ in Table AA is G.

362. The MBM of any one of embodiments 327 to 361, wherein the aminoacid designated X₁₄ in Table AA is R.

363. The MBM of any one of embodiments 327 to 361, wherein the aminoacid designated X₁₄ in Table AA is N.

364. The MBM of any one of embodiments 327 to 363, wherein the aminoacid designated X₁₅ in Table AA is D.

365. The MBM of any one of embodiments 327 to 363, wherein the aminoacid designated X₁₅ in Table AA is E.

366. The MBM of any one of embodiments 327 to 363, wherein the aminoacid designated X₁₅ in Table AA is L.

367. The MBM of any one of embodiments 327 to 366, wherein the aminoacid designated X₁₆ in Table AA is G.

368. The MBM of any one of embodiments 327 to 366, wherein the aminoacid designated X₁₆ in Table AA is N.

369. The MBM of any one of embodiments 327 to 366, wherein the aminoacid designated X₁₆ in Table AA is E.

370. The MBM of any one of embodiments 327 to 369, wherein the aminoacid designated X₁₇ in Table AA is R.

371. The MBM of any one of embodiments 327 to 369, wherein the aminoacid designated X₁₇ in Table AA is S.

372. The MBM of any one of embodiments 327 to 371, wherein the aminoacid designated X₁₈ in Table AA is V.

373. The MBM of any one of embodiments 327 to 371, wherein the aminoacid designated X₁₈ in Table AA is T.

374. The MBM of any one of embodiments 327 to 373, wherein the aminoacid designated X₁₉ in Table AA is N.

375. The MBM of any one of embodiments 327 to 373, wherein the aminoacid designated X₁₉ in Table AA is T.

376. The MBM of any one of embodiments 327 to 375, wherein the aminoacid designated X₂₀ in Table AA is R.

377. The MBM of any one of embodiments 327 to 375, wherein the aminoacid designated X₂₀ in Table AA is L.

378. The MBM of any one of embodiments 327 to 377, wherein the aminoacid designated X₂₁ in Table AA is F.

379. The MBM of any one of embodiments 327 to 377, wherein the aminoacid designated X₂₁ in Table AA is E.

380. The MBM of any one of embodiments 327 to 379, wherein the aminoacid designated X₂₂ in Table AA is S.

381. The MBM of any one of embodiments 327 to 379, wherein the aminoacid designated X₂₂ in Table AA is Y.

382. The MBM of any one of embodiments 327 to 381, wherein the aminoacid designated X₂₃ in Table AA is S.

383. The MBM of any one of embodiments 327 to 381, wherein the aminoacid designated X₂₃ in Table AA is Y.

384. The MBM of any one of embodiments 327 to 383, wherein the aminoacid designated X₂₄ in Table AA is S.

385. The MBM of any one of embodiments 327 to 383, wherein the aminoacid designated X₂₄ in Table AA is A.

386. The MBM of any one of embodiments 327 to 385, wherein the aminoacid designated X₂₅ in Table AA is H.

387. The MBM of any one of embodiments 327 to 385, wherein the aminoacid designated X₂₅ in Table AA is T.

388. The MBM of any one of embodiments 327 to 387, wherein the aminoacid designated X₂₆ in Table AA is F.

389. The MBM of any one of embodiments 327 to 387, wherein the aminoacid designated X₂₆ in Table AA is Y.

390. The MBM of any one of embodiments 327 to 389, wherein the aminoacid designated X₂₇ in Table AA is W.

391. The MBM of any one of embodiments 327 to 389, wherein the aminoacid designated X₂₇ in Table AA is Y.

392. The MBM of any one of embodiments 327 to 391, wherein ABM2comprises the CDR-H1 sequence C1-1.

393. The MBM of any one of embodiments 327 to 391, wherein ABM2comprises the CDR-H1 sequence C1-2.

394. The MBM of any one of embodiments 327 to 391, wherein ABM2comprises the CDR-H1 sequence C1-3.

395. The MBM of any one of embodiments 327 to 391, wherein ABM2comprises the CDR-H1 sequence C_(1-4.)

396. The MBM of any one of embodiments 327 to 395, wherein ABM2comprises the CDR-H2 sequence C1-5.

397. The MBM of any one of embodiments 327 to 395, wherein ABM2comprises the CDR-H2 sequence C1-6.

398. The MBM of any one of embodiments 327 to 395, wherein ABM2comprises the CDR-H2 sequence C1-7.

399. The MBM of any one of embodiments 327 to 398, wherein ABM2comprises the CDR-H3 sequence C1-8.

400. The MBM of any one of embodiments 327 to 398, wherein ABM2comprises the CDR-H3 sequence C1-9.

401. The MBM of any one of embodiments 327 to 398, wherein ABM2comprises the CDR-H3 sequence C1-10.

402. The MBM of any one of embodiments 327 to 398, wherein ABM2comprises the CDR-H3 sequence C1-11.

403. The MBM of any one of embodiments 327 to 402, wherein ABM2comprises the CDR-L1 sequence C1-12.

404. The MBM of any one of embodiments 327 to 402, wherein ABM2comprises the CDR-L1 sequence C1-13.

405. The MBM of any one of embodiments 327 to 402, wherein ABM2comprises the CDR-L1 sequence C1-14.

406. The MBM of any one of embodiments 327 to 402, wherein ABM2comprises the CDR-L1 sequence C1-15.

407. The MBM of any one of embodiments 327 to 402, wherein ABM2comprises the CDR-L1 sequence C1-16.

408. The MBM of any one of embodiments 327 to 402, wherein ABM2comprises the CDR-L1 sequence C1-17.

409. The MBM of any one of embodiments 327 to 408, wherein ABM2comprises the CDR-L2 sequence C1-18.

410. The MBM of any one of embodiments 327 to 408, wherein ABM2comprises the CDR-L2 sequence C1-19.

411. The MBM of any one of embodiments 327 to 410, wherein ABM2comprises the CDR-L3 sequence C1-20.

412. The MBM of any one of embodiments 327 to 410, wherein ABM2comprises the CDR-L3 sequence C1-21.

413. The MBM of any one of embodiments 327 to 410, wherein ABM2comprises the CDR-L3 sequence C1-22.

414. The MBM of any one of embodiments 327 to 410, wherein ABM2comprises the CDR-L3 sequence C1-23.

415. The MBM of embodiment 326, wherein ABM2 comprises a CDR-H1sequence, a CDR-H2 sequence, a CDR-H3 sequence, a CDR-L1 sequence, aCDR-L2 sequence, and a CDR-L3 sequence set forth in Table AB.

416. The MBM of embodiment 415, wherein the amino acid designated X₂₈ inTable AB is V.

417. The MBM of embodiment 415, wherein the amino acid designated X₂₈ inTable AB is I.

418. The MBM of any one of embodiments 415 to 417, wherein the aminoacid designated X₂₉ in Table AB is F.

419. The MBM of any one of embodiments 415 to 417, wherein the aminoacid designated X₂₉ in Table AB is Y.

420. The MBM of any one of embodiments 415 to 419, wherein the aminoacid designated X₃₀ in Table AB is N.

421. The MBM of any one of embodiments 415 to 419, wherein the aminoacid designated X₃₀ in Table AB is S.

422. The MBM of any one of embodiments 415 to 421, wherein the aminoacid designated X₃₁ in Table AB is A.

423. The MBM of any one of embodiments 415 to 421, wherein the aminoacid designated X₃₁ in Table AB is S.

424. The MBM of any one of embodiments 415 to 423, wherein the aminoacid designated X₃₂ in Table AB is T.

425. The MBM of any one of embodiments 415 to 423, wherein the aminoacid designated X₃₂ in Table AB is K.

426. The MBM of any one of embodiments 415 to 425, wherein the aminoacid designated X₃₃ in Table AB is T.

427. The MBM of any one of embodiments 415 to 425, wherein the aminoacid designated X₃₃ in Table AB is A.

428. The MBM of any one of embodiments 415 to 427, wherein the aminoacid designated X₃₄ in Table AB is S.

429. The MBM of any one of embodiments 415 to 427, wherein the aminoacid designated X₃₄ in Table AB is R.

430. The MBM of any one of embodiments 415 to 429, wherein the aminoacid designated X₃₅ in Table AB is N.

431. The MBM of any one of embodiments 415 to 429, wherein the aminoacid designated X₃₅ in Table AB is G.

432. The MBM of any one of embodiments 415 to 431, wherein the aminoacid designated X₃₆ in Table AB is S.

433. The MBM of any one of embodiments 415 to 431, wherein the aminoacid designated X₃₆ in Table AB is A.

434. The MBM of any one of embodiments 415 to 433, wherein the aminoacid designated X₃₇ in Table AB is A.

435. The MBM of any one of embodiments 415 to 433, wherein the aminoacid designated X₃₇ in Table AB is T.

436. The MBM of any one of embodiments 415 to 433, wherein the aminoacid designated X₃₇ in Table AB is S.

437. The MBM of any one of embodiments 415 to 436, wherein the aminoacid designated X₃₈ in Table AB is N.

438. The MBM of any one of embodiments 415 to 436, wherein the aminoacid designated X₃₈ in Table AB is D.

439. The MBM of any one of embodiments 415 to 438, wherein the aminoacid designated X₃₉ in Table AB is N.

440. The MBM of any one of embodiments 415 to 438, wherein the aminoacid designated X₃₉ in Table AB is K.

441. The MBM of any one of embodiments 415 to 440, wherein the aminoacid designated X₄₀ in Table AB is D.

442. The MBM of any one of embodiments 415 to 440, wherein the aminoacid designated X₄₀ in Table AB is N.

443. The MBM of any one of embodiments 415 to 442, wherein the aminoacid designated X₄₁ in Table AB is H.

444. The MBM of any one of embodiments 415 to 442, wherein the aminoacid designated X₄₁ in Table AB is N.

445. The MBM of any one of embodiments 415 to 444, wherein the aminoacid designated X₄₂ in Table AB is Q.

446. The MBM of any one of embodiments 415 to 444, wherein the aminoacid designated X₄₂ in Table AB is E.

447. The MBM of any one of embodiments 415 to 446, wherein the aminoacid designated X₄₃ in Table AB is R.

448. The MBM of any one of embodiments 415 to 446, wherein the aminoacid designated X₄₃ in Table AB is S.

449. The MBM of any one of embodiments 415 to 446, wherein the aminoacid designated X₄₃ in Table AB is G.

450. The MBM of any one of embodiments 415 to 449, wherein ABM2comprises the CDR-H1 sequence C2-1.

451. The MBM of any one of embodiments 415 to 449, wherein ABM2comprises the CDR-H1 sequence C2-2.

452. The MBM of any one of embodiments 415 to 449, wherein ABM2comprises the CDR-H1 sequence C2-3.

453. The MBM of any one of embodiments 415 to 449, wherein ABM2comprises the CDR-H1 sequence C2-4.

454. The MBM of any one of embodiments 415 to 453, wherein ABM2comprises the CDR-H2 sequence C2-5.

455. The MBM of any one of embodiments 415 to 453, wherein ABM2comprises the CDR-H2 sequence C2-6.

456. The MBM of any one of embodiments 415 to 453, wherein ABM2comprises the CDR-H2 sequence C2-7.

457. The MBM of any one of embodiments 415 to 456, wherein ABM2comprises the CDR-H3 sequence C2-8.

458. The MBM of any one of embodiments 415 to 456, wherein ABM2comprises the CDR-H3 sequence C2-9.

459. The MBM of any one of embodiments 415 to 458, wherein ABM2comprises the CDR-L1 sequence C2-10.

460. The MBM of any one of embodiments 415 to 458, wherein ABM2comprises the CDR-L1 sequence C2-11.

461. The MBM of any one of embodiments 415 to 458, wherein ABM2comprises the CDR-L1 sequence C2-12.

462. The MBM of any one of embodiments 415 to 461, wherein ABM2comprises the CDR-L2 sequence C2-13.

463. The MBM of any one of embodiments 415 to 461, wherein ABM2comprises the CDR-L2 sequence C2-14.

464. The MBM of any one of embodiments 415 to 461, wherein ABM2comprises the CDR-L2 sequence C2-15.

465. The MBM of any one of embodiments 415 to 464, wherein ABM2comprises the CDR-L3 sequence C2-16.

466. The MBM of any one of embodiments 415 to 464, wherein ABM2comprises the CDR-L3 sequence C2-17.

467. The MBM of embodiment 326, wherein ABM2 comprises a CDR-H1sequence, a CDR-H2 sequence, a CDR-H3 sequence, a CDR-L1 sequence, aCDR-L2 sequence, and a CDR-L3 sequence set forth in Table AC.

468. The MBM of embodiment 467, wherein the amino acid designated X₄₄ inTable AC is G.

469. The MBM of embodiment 467, wherein the amino acid designated X₄₄ inTable AC is A.

470. The MBM of any one of embodiments 467 to 469, wherein the aminoacid designated X₄₅ in Table AC is H.

471. The MBM of any one of embodiments 467 to 469, wherein the aminoacid designated X₄₅ in Table AC is N.

472. The MBM of any one of embodiments 467 to 471, wherein the aminoacid designated X₄₆ in Table AC is D.

473. The MBM of any one of embodiments 467 to 471, wherein the aminoacid designated X₄₆ in Table AC is G.

474. The MBM of any one of embodiments 467 to 473, wherein the aminoacid designated X₄₇ in Table AC is A.

475. The MBM of any one of embodiments 467 to 473, wherein the aminoacid designated X₄₇ in Table AC is G.

476. The MBM of any one of embodiments 467 to 475, wherein the aminoacid designated X₄₈ in Table AC is N.

477. The MBM of any one of embodiments 467 to 475, wherein the aminoacid designated X₄₈ in Table AC is K.

478. The MBM of any one of embodiments 467 to 477, wherein the aminoacid designated X₄₉ in Table AC is V.

479. The MBM of any one of embodiments 467 to 477, wherein the aminoacid designated X₄₉ in Table AC is A.

480. The MBM of any one of embodiments 467 to 479, wherein the aminoacid designated X₅₀ in Table AC is N.

481. The MBM of any one of embodiments 467 to 479, wherein the aminoacid designated X₅₀ in Table AC is V.

482. The MBM of any one of embodiments 467 to 481, wherein the aminoacid designated X₅₁ in Table AC is A.

483. The MBM of any one of embodiments 467 to 481, wherein the aminoacid designated X₅₁ in Table AC is V.

484. The MBM of any one of embodiments 467 to 483, wherein the aminoacid designated X₅₂ in Table AC is Y.

485. The MBM of any one of embodiments 467 to 483, wherein the aminoacid designated X₅₂ in Table AC is F.

486. The MBM of any one of embodiments 467 to 485, wherein the aminoacid designated X₅₃ in Table AC is I.

487. The MBM of any one of embodiments 467 to 485, wherein the aminoacid designated X₅₃ in Table AC is V.

488. The MBM of any one of embodiments 467 to 487, wherein the aminoacid designated X₅₄ in Table AC is I.

489. The MBM of any one of embodiments 467 to 487, wherein the aminoacid designated X₅₄ in Table AC is H.

490. The MBM of any one of embodiments 467 to 489, wherein ABM2comprises the CDR-H1 sequence C3-1.

491. The MBM of any one of embodiments 467 to 489, wherein ABM2comprises the CDR-H1 sequence C3-2.

492. The MBM of any one of embodiments 467 to 489, wherein ABM2comprises the CDR-H1 sequence C3-3.

493. The MBM of any one of embodiments 467 to 489, wherein ABM2comprises the CDR-H1 sequence C3-4.

494. The MBM of any one of embodiments 467 to 493, wherein ABM2comprises the CDR-H2 sequence C3-5.

495. The MBM of any one of embodiments 467 to 493, wherein ABM2comprises the CDR-H2 sequence C3-6.

496. The MBM of any one of embodiments 467 to 493, wherein ABM2comprises the CDR-H2 sequence C3-7.

497. The MBM of any one of embodiments 467 to 496, wherein ABM2comprises the CDR-H3 sequence C3-8.

498. The MBM of any one of embodiments 467 to 496, wherein ABM2comprises the CDR-H3 sequence C3-9.

499. The MBM of any one of embodiments 467 to 498, wherein ABM2comprises the CDR-L1 sequence C3-10.

500. The MBM of any one of embodiments 467 to 498, wherein ABM2comprises the CDR-L1 sequence C3-11.

501. The MBM of any one of embodiments 467 to 498, wherein ABM2comprises the CDR-L1 sequence C3-12.

SO₂. The MBM of any one of embodiments 467 to 501, wherein ABM2comprises the CDR-L2 sequence C3-13.

503. The MBM of any one of embodiments 467 to 501, wherein ABM2comprises the CDR-L2 sequence C3-14.

504. The MBM of any one of embodiments 467 to 503, wherein ABM2comprises the CDR-L3 sequence C3-15.

505. The MBM of any one of embodiments 467 to 503, wherein ABM2comprises the CDR-L3 sequence C3-16.

506. The MBM of embodiment 151, wherein ABM2 comprises CDR-H1 CDR-H2,and CDR-H3 sequences set forth in Table AD-1, Table AE-1, Table AF-1,Table AG-1, Table AH-1, or Table AI-1, and the corresponding CDR-L1,CDR-L2, and CDR-L3 sequences set forth in Table AD-2, Table AE-2, TableAF-2, Table AG-2, Table AH-2, or Table AI-2, respectfully.

507. The MBM of embodiment 506, wherein ABM2 comprises CDR-H1, CDR-H2,and CDR-H3 sequences set forth in Table AD-1 and the correspondingCDR-L1, CDR-L2, and CDR-L3 sequences set forth in Table AD-2.

508. The MBM of embodiment 506, wherein ABM2 comprises CDR-H1, CDR-H2,and CDR-H3 sequences set forth in Table AE-1 and the correspondingCDR-L1, CDR-L2, and CDR-L3 sequences set forth in Table AE-2.

509. The MBM of embodiment 506, wherein ABM2 comprises CDR-H1, CDR-H2,and CDR-H3 sequences set forth in Table AF-1 and the correspondingCDR-L1, CDR-L2, and CDR-L3 sequences set forth in Table AF-2.

510. The MBM of embodiment 506, wherein ABM2 comprises CDR-H1, CDR-H2,and CDR-H3 sequences set forth in Table AG-1 and the correspondingCDR-L1, CDR-L2, and CDR-L3 sequences set forth in Table AG-2.

511. The MBM of embodiment 506, wherein ABM2 comprises CDR-H1, CDR-H2,and CDR-H3 sequences set forth in Table AH-1 and the correspondingCDR-L1, CDR-L2, and CDR-L3 sequences set forth in Table AH-2.

512. The MBM of embodiment 506, wherein ABM2 comprises CDR-H1, CDR-H2,and CDR-H3 sequences set forth in Table AI-1 and the correspondingCDR-L1, CDR-L2, and CDR- L3 sequences set forth in Table AI-2.

513. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV292.

514. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV123.

515. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof Sp10b.

516. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV453.

517. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV229.

518. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV110.

519. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV832.

520. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV589.

521. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV580.

522. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV567.

523. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof NOV221.

524. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a—bkm1.

525. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11a—bkm2.

526. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a—hz0.

527. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A—HZ1.

528. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_sansP™_hz1.

529. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_sansP™_rat.

530. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_YY.

531. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_P11A_VHVL_SS.

532. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VHVL_WS.

533. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SW.

534. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VHVL_TT.

535. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VHVL_TW.

536. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VHVL_TW.

537. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A VH3_VLK_3.

538. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2.

539. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1.

540. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH5_VK2.

541. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp9aFW1_VL_VH_S56G.

542. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP9AFW4_VL_VH_S56G.

543. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp9aFW1_VL_VH.

544. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp9aFW4_VLVH.

545. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp9arabtor_VHVL.

546. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp9arabtor_VLVH.

547. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_YY_SANSP™.

548. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_YY_SANSP™_Y.

549. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_YY_SANSP™_S.

550. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_YY_Y.

551. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_YY_s.

552. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SS_SANSP™.

553. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SS_SANSP™_Y.

554. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SS_SANSP™_S.

555. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SS_Y.

556. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SS_S.

557. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SS_SANSP™.

558. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_WS_SANSP™_Y.

559. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_WS_SANSP™_S.

560. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_WS_Y.

561. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_WS_S.

562. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_WS_SANSP™.

563. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SW_SANSP™_Y.

564. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SW_SANSP™_S.

565. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SW_Y.

566. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SW_S.

567. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_SW_SANSP™.

568. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_TW_SANSP™_Y.

569. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_TW_SANSP™_S.

570. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_TW_.

571. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_TW_S.

572. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_TW_SANSP™.

573. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL_TT_SANSP™_Y.

574. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL—TT—SANSP™_S.

575. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL—TT_Y.

576. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL—TT_S.

577. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VHVL—TT_SANSP™.

578. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11AVH3_VLK_3_Y.

579. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11AVH3_VLK_3_S. 580. The MBM of any one of embodiments 507 to512, wherein ABM2 comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, andCDR-L3 sequences of CD3_SP11AVH3_VLK_3_Y_P™.

581. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11AVH3 VLK 3 S P™. 582. The MBM of any one of embodiments 507to 512, wherein ABM2 comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2,and CDR-L3 sequences of CD3_SP11AVH3_VLK_3_Y_SW.

583. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11AVH3 VLK 3 S SW. 584. The MBM of any one of embodiments 507to 512, wherein ABM2 comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2,and CDR-L3 sequences of CD3_SP11AVH3_VLK_3_Y_P™_SW.

585. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11AVH3 VLK 3 S SWP™. 586. The MBM of any one of embodiments 507to 512, wherein ABM2 comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2,and CDR-L3 sequences of CD3 SP11AVH3_VLK SWP™. 587. The MBM of any oneof embodiments 507 to 512, wherein ABM2 comprises CDR-H1, CDR-H2,CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences of CD3 SP11AVH3 VLK 3 SW.588. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_Y.

589. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_S.

590. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_Y_P™.

591. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_S_P™.

592. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_Y_SW.

593. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_S_SW.

594. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_Y_P™.

595. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_S_P™_SW.

596. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_SW.

597. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_sp11a_VH1_VK2_SW P™.

598. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1_Y.

599. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1_S.

600. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1_Y_P™.

601. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1_S_P™.

602. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1_Y_SW.

603. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3_VLK1_S_SW.

604. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3 VLK1 Y_P™.

605. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3 VLK1 S_P™_SW.

606. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11A_VH3VLK1P™_SW.

607. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH3 VLK1 SW.

608. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH5_VK2_Y.

609. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH5_VK2_S.

610. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11A VH5 VK2 Y P™.

_ — — — 611. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11A_VH5 VK2 S_P™.

612. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11A VH5 VK2 Y SW. 613. The MBM of any one of embodiments 507 to512, wherein ABM2 comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, andCDR-L3 sequences of CD3_SP11A_VH5 VK2 S_SW.

614. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11A VH5 VK2 Y P™SW.

615. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3 SP11A_VH5 VK2 S_P™_SW.

616. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH5 VK2 P™_SW.

617. The MBM of any one of embodiments 507 to 512, wherein ABM2comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencesof CD3_SP11A_VH5 VK2 SW.

618. The MBM of embodiment 506, wherein ABM2 comprises a heavy chainvariable sequence set forth in Table AJ-1 and the corresponding lightchain variable sequence set forth in Table AJ-2.

619. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV292.

620. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV123.

621. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of Sp10b.

622. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV453.

623. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV229.

624. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV110.

625. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV832.

626. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV589.

627. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV580.

628. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV567.

629. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of NOV221.

630. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_bkm1.

631. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11a_bkm2.

632. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_hz0.

633. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_HZ1.

634. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_sansP™_hz1.

635. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_sansP™_rat.

636. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_YY.

637. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VHVL_SS.

638. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VHVL_WS.

639. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SW.

640. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VHVL_TT.

641. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VHVL_TW.

642. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VHVL_VVT.

643. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of CD3_SP11AVH3_VLK_3.

644. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2.

645. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1.

646. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2.

647. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp9aFW1_VL_VH_S56G.

648. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP9AFW4_VL_VH_S56G.

649. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp9aFW1_VL_VH.

650. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp9aFW4_VLVH.

651. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp9arabtor_VHVL.

652. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp9arabtor_VLVH.

653. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_YY_SANSP™.

654. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_YY_SANSP™_Y.

655. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_YY_SANSP™_S.

656. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_YY_Y.

657. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_YY_s.

658. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SS_SANSP™.

659. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SS_SANSP™_Y.

660. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SS_SANSP™_S.

661. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SS_Y.

662. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SS_S.

663. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SS _SANSP™.

664. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_WS SANSP™_Y.

665. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_WS _SANSP™_S.

666. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_WS_.

667. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_WS _S.

668. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_WS _SANSP™.

669. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SW SANSP™_Y.

670. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SW _SANSP™_S.

671. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SW_.

672. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SW _S.

673. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_SW SANSP™.

674. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TW SANSP™_Y.

675. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TW SANSP™_S.

676. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TW_.

677. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TW_S.

678. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TW SANSP™.

679. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TT SANSP™_Y.

680. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TT_SANSP™_S.

681. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TT_Y.

682. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TT_S.

683. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VHVL_TT_SANSP™.

684. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_Y.

685. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_S.

686. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_Y_P™.

687. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_S_P™.

688. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_Y_SW.

689. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_S_SW.

690. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_Y_P™_SW.

691. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of CD3 SP11AVH3VLK 3 S SWP™.

_ — — — 692. The MBM of embodiment 618, wherein ABM2 comprises the heavychain variable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_SWP™.

693. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11AVH3_VLK_3_SW.

694. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_Y.

695. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_S.

696. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_Y_P™.

697. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_S_P™.

698. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_Y_SW.

699. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_S_SW.

700. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_Y_P™.

701. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_S_P™_SW.

702. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_SW.

703. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_sp11a_VH1_VK2_SW P™.

704. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_Y.

705. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_S.

706. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_Y_P™.

707. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_S_P™.

708. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_Y_SW.

709. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_S_SW.

710. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_Y_P™.

711. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_S_P™_SW.

712. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1P™_SW.

713. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH3_VLK1_SW.

714. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_Y.

715. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_S.

716. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_Y_P™.

717. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_S_P™.

718. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_Y_SW.

719. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_S_SW.

720. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence of CD3 SP11A VH5VK2 Y P™SW.

_ — — — — 721. The MBM of embodiment 618, wherein ABM2 comprises theheavy chain variable sequence and the light chain variable sequence ofCD3 SP11A_VH5 VK2 S_P™_SW.

722. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_P™_SW.

723. The MBM of embodiment 618, wherein ABM2 comprises the heavy chainvariable sequence and the light chain variable sequence ofCD3_SP11A_VH5_VK2_SW.

724. The MBM of any one of embodiments 1 to 150, wherein the componentof the TCR complex is TCR-a, TCR-13, or a TCR-a, 13 dimer.

725. The MBM of embodiment 724, wherein the component of the TCR complexis TCR-a.

726. The MBM of embodiment 724, wherein the component of the TCR complexis

TCR-13.

727. The MBM of embodiment 724, wherein the component of the TCR complexis a TCR-α/β dimer.

728. The MBM of embodiment 724, wherein ABM2 comprises the CDR sequencesof BMA031.

729. The MBM of embodiment 728, wherein the CDR sequences are defined byKabat numbering.

730. The MBM of embodiment 728, wherein the CDR sequences are defined byChothia numbering.

731. The MBM of embodiment 728, wherein the CDR sequences are defined bya combination of Kabat and Chothia numbering.

732. The MBM of embodiment 728, wherein ABM2 comprises the heavy andlight chain variable sequences of BMA031.

733. The MBM of any one of embodiments 1 to 150, wherein the componentof the TCR complex is TCR-γ, TCR-δ, or a TCR-γ/δ dimer.

734. The MBM of embodiment 733, wherein the component of the TCR complexis TCR-γ.

735. The MBM of embodiment 733, wherein the component of the TCR complexis TCR-γ/δ.

736. The MBM of embodiment 733, wherein the component of the TCR complexis a TCR-γ/δ dimer.

737. The MBM of embodiment 733, wherein ABM2 comprises the CDR sequencesof OTCS1.

738. The MBM of embodiment 737, wherein the CDR sequences are defined byKabat numbering.

739. The MBM of embodiment 737, wherein the CDR sequences are defined byChothia numbering.

740. The MBM of embodiment 737, wherein the CDR sequences are defined bya combination of Kabat and Chothia numbering.

741. The MBM of embodiment 737, wherein ABM2 comprises the heavy andlight chain variable sequences of OTCS1.

742. The MBM of any one of embodiments 1 to 741, wherein ABM3 bindsspecifically to human CD2.

743. The MBM of embodiment 742, wherein ABM3 is a non-immunoglobulinscaffold based ABM.

744. The MBM of embodiment 743, wherein ABM3 is a Kunitz domain, anAdnexin, an Affibody, a DARPin, an Avimer, an Anticalin, a Lipocalin, aCentyrin, a Versabody, a Knottin, an Adnectin, a Pronectin, anAffitin/Nanofitin, an Affilin, an Atrimer/Tetranectin, a bicyclicpeptide, a cys-knot, a Fn3 scaffold, an Obody, a Tn3, an Affimer, BD, anAdhiron, a Duocalin, an Alphabody, an Armadillo Repeat Protein, aRepebody, or a Fynomer.

745. The MBM of embodiment 743, wherein ABM3 comprises a receptorbinding domain of a CD2 ligand.

746. The MBM of embodiment 745, wherein the CD2 ligand is CD58. 747. TheMBM of embodiment 745, wherein the CD2 ligand is CD48. 748. The MBM ofembodiment 745, wherein ABM3 is a CD58 moiety. 749. The MBM ofembodiment 748, wherein the CD58 moiety comprises the amino acidsequence of CD58-1 as set forth in Table 15.

750. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-2 as set forth in Table 15.

751. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-3 as set forth in Table 15.

752. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-4 as set forth in Table 15.

753. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-5 as set forth in Table 15.

754. The MBM of embodiment 753, wherein the amino acid designated as Bis a phenylalanine.

755. The MBM of embodiment 753, wherein the amino acid designated as Bis a serine.

756. The MBM of any one of embodiments 753 to 755, wherein the aminoacid designated as J is a valine.

757. The MBM of any one of embodiments 753 to 755, wherein the aminoacid designated as J is a lysine.

758. The MBM of any one of embodiments 753 to 757, wherein the aminoacid designated as 0 is a valine.

759. The MBM of any one of embodiments 753 to 757, wherein the aminoacid designated as 0 is a glutamine.

760. The MBM of any one of embodiments 753 to 759, wherein the aminoacid designated as U is a valine.

761. The MBM of any one of embodiments 753 to 759, wherein the aminoacid designated as U is a lysine.

762. The MBM of any one of embodiments 753 to 761, wherein the aminoacid designated as X is a threonine.

763. The MBM of any one of embodiments 753 to 761, wherein the aminoacid designated as X is a serine.

764. The MBM of any one of embodiments 753 to 763, wherein the aminoacid designated as Z is a leucine.

765. The MBM of any one of embodiments 753 to 763, wherein the aminoacid designated as Z is a glycine.

766. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-6 as set forth in Table 15.

767. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-7 as set forth in Table 15.

768. The MBM of embodiment 767, wherein the amino acid designated as Jis a valine.

769. The MBM of embodiment 767, wherein the amino acid designated as Jis a lysine.

770. The MBM of any one of embodiments 767 to 769, wherein the aminoacid designated as 0 is a valine.

771. The MBM of any one of embodiments 767 to 769, wherein the aminoacid designated as 0 is a glutamine.

772. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-8 as set forth in Table 15.

773. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-9 as set forth in Table 15.

774. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-10 as set forth in Table 15.

775. The MBM of embodiment 748, wherein the CD58 moiety comprises theamino acid sequence of CD58-11 as set forth in Table 15.

776. The MBM of embodiment 745, wherein ABM3 is a CD48 moiety. 777. TheMBM of embodiment 776, wherein the CD48 moiety has at least 70% sequenceidentity to amino acids 27-220 of the amino acid sequence of Uniprotidentifier P09326.

778. The MBM of embodiment 776, wherein the CD48 moiety has at least 80%sequence identity to amino acids 27-220 of the amino acid sequenceofUniprot identifier P09326.

779. The MBM of embodiment 776, wherein the CD48 moiety has at least 90%sequence identity to amino acids 27-220 of the amino acid sequence ofUniprot identifier P09326.

780. The MBM of embodiment 776, wherein the CD48 moiety has at least 95%sequence identity to amino acids 27-220 of the amino acid sequence ofUniprot identifier P09326.

781. The MBM of embodiment 776, wherein the CD48 moiety has at least 99%sequence identity to amino acids 27-220 of the amino acid sequence ofUniprot identifier P09326.

782. The MBM of embodiment 742, wherein ABM3 is an immunoglobulinscaffold based ABM.

783. The MBM of embodiment 782, wherein ABM3 is an antibody, an antibodyfragment, an scFv, a dsFv, a Fv, a Fab, an scFab, a (Fab′)2, a singledomain antibody (SDAB), a VH or VL domain, or a camelid VHH domain.

784. The MBM of embodiment 783, wherein ABM3 is an antibody or anantigen- binding domain thereof.

785. The MBM of embodiment 783, wherein ABM3 is an scFv. 786. The MBM ofembodiment 783, wherein ABM3 is a Fab. 787. The MBM of embodiment 786,wherein ABM3 is a Fab heterodimer. 788. The MBM of any one ofembodiments 782 to 787, wherein ABM3 comprises the CDR sequences ofCD2-1.

789. The MBM of embodiment 788, wherein ABM3 comprises the heavy andlight chain variable sequences of CD2-1.

790. The MBM of embodiment 788, wherein ABM3 comprises the heavy andlight chain variable sequences of hu1CD2-1.

791. The MBM of embodiment 788, wherein ABM3 comprises the heavy andlight chain variable sequences of hu2CD2-1.

792. The MBM of embodiment 788, wherein ABM3 comprises the CDR sequencesof Medi 507.

793. The MBM of embodiment 792, wherein ABM3 comprises the heavy andlight chain variable sequences of Medi 507.

794. The MBM of any one of embodiments 1 to 741, wherein ABM3 bindsspecifically to a human TAA.

795. The MBM of embodiment 794, wherein ABM3 is a non-immunoglobulinscaffold based ABM.

796. The MBM of embodiment 795, wherein if TAA is a receptor, ABM3comprises a receptor binding domain of a ligand of the receptor, and ifTAA is a ligand, ABM3 comprises a ligand binding domain of a receptor ofthe ligand.

797. The MBM of embodiment 795, wherein ABM1 is a Kunitz domain, anAdnexin, an Affibody, a DARPin, an Avimer, an Anticalin, a Lipocalin, aCentyrin, a Versabody, a Knottin, an Adnectin, a Pronectin, anAffitin/Nanofitin, an Affilin, an Atrimer/Tetranectin, a bicyclicpeptide, a cys-knot, a Fn3 scaffold, an Obody, a Tn3, an Affimer, BD, anAdhiron, a Duocalin, an Alphabody, an Armadillo Repeat Protein, aRepebody, or a Fynomer.

798. The MBM of embodiment 794, wherein ABM3 is an immunoglobulinscaffold based ABM.

799. The MBM of embodiment 798, wherein ABM3 is an antibody, an antibodyfragment, an scFv, a dsFv, a Fv, a Fab, an scFab, a (Fab′)2, a singledomain antibody (SDAB), a VH or VL domain, or a camelid VHH domain.

800. The MBM of embodiment 799, wherein ABM3 is an antibody or anantigen- binding domain thereof.

801. The MBM of embodiment 799, wherein ABM3 is an scFv.

802. The MBM of embodiment 799, wherein ABM3 is a Fab.

803. The MBM of embodiment 802, wherein ABM3 is a Fab heterodimer.

804. The MBM of embodiments 794 to 803, wherein the TAA is a TAAexpressed on cancerous B cells that are B cell-derived plasma cells.

805. The MBM of embodiments 794 to 803, wherein the TAA is a TAAexpressed on cancerous B cells that are not plasma cells.

806. The MBM of embodiments 794 to 805, wherein the TAA is selected fromCD19, CD20, CD22, CD123, CD33, CLL1, CD138, CS1, CD38, CD133, FLT3,CD52, TNFRSF13C, TNFRSF13B, CXCR4, PD-L1, LY9, CD200, FCGR2B, CD21,CD23, CD24, CD4OL, CD72, CD79a, and CD79b.

807. The MBM of embodiment 806, wherein the TAA is CD19.

808. The MBM of embodiment 806, wherein the TAA is CD20.

809. The MBM of embodiment 806, wherein the TAA is CD22.

810. The MBM of embodiment 806, wherein the TAA is CD123.

811. The MBM of embodiment 806, wherein the TAA is CD33.

812. The MBM of embodiment 806, wherein the TAA is CLL1.

813. The MBM of embodiment 806, wherein the TAA is CD138.

814. The MBM of embodiment 806, wherein the TAA is CS1.

815. The MBM of embodiment 806, wherein the TAA is CD38.

816. The MBM of embodiment 806, wherein the TAA is CD133.

817. The MBM of embodiment 806, wherein the TAA is FLT3.

818. The MBM of embodiment 806, wherein the TAA is CD52.

819. The MBM of embodiment 806, wherein the TAA is TNFRSF13C.

820. The MBM of embodiment 806, wherein the TAA is TNFRSF13B.

821. The MBM of embodiment 806, wherein the TAA is CXCR4.

822. The MBM of embodiment 806, wherein the TAA is PD-L1.

823. The MBM of embodiment 806, wherein the TAA is LY9.

824. The MBM of embodiment 806, wherein the TAA is CD200.

825. The MBM of embodiment 806, wherein the TAA is FCGR2B.

826. The MBM of embodiment 806, wherein the TAA is CD21.

827. The MBM of embodiment 806, wherein the TAA is CD23.

828. The MBM of embodiment 806, wherein the TAA is CD24.

829. The MBM of embodiment 806, wherein the TAA is CD4OL.

830. The MBM of embodiment 806, wherein the TAA is CD72.

831. The MBM of embodiment 806, wherein the TAA is CD79a.

832. The MBM of embodiment 806, wherein the TAA is CD79b.

833. The MBM of embodiment 807, wherein ABM3 comprises:

(a) a CDR-H1 having the amino acid sequence of the CDR designated as

CD19-H1;

(b) a CDR-H2 having the amino acid sequence of any one of the CDRsdesignated as CD19-H₂A, HD19-H₂B, CD19-H₂C and CD19-H₂D;

(c) a CDR-H3 having the amino acid sequence of the CDR designated as

CD19-H3;

(d) a CDR-L1 having the amino acid sequence of the CDR designated as

CD19-L1; (e) a CDR-L2 having the amino acid sequence of the CDRdesignated as

CD19-L2; and (f) a CDR-L3 having the amino acid sequence of the CDRdesignated as

CD19-L23.

834. The MBM of embodiment 833, wherein ABM3 comprises:

(a) a VH having the amino acid sequence of any one of the VH'sdesignated as CD19-VHA, CD19-VHB, CD19-VHC, and CD19-VHD; and (b) a VLhaving the amino acid sequence of any one of the VL's designated asCD19-VLA and CD19-VLB.

835. The MBM of embodiment 807, wherein ABM3 comprises heavy chain CDRshaving the amino acid sequences of CD19-H1, CD19-H₂A, and CD19-H3 as setforth in Table 17 and light chain CDRs having the amino acid sequencesof CD19-L1, CD19-L2, and CD19- L3 as set forth in Table 17.

836. The MBM of embodiment 807, wherein ABM3 comprises a heavy chainvariable region having the amino acid sequences of VHA as set forth inTable 17 and a light chain variable region having the amino acidsequences of VLA as set forth in Table 17.

837. The MBM of embodiment 807, wherein ABM3 comprises heavy chain CDRshaving the amino acid sequences of CD19-H1, CD19-H₂B, and CD19-H3 as setforth in Table 17 and light chain CDRs having the amino acid sequencesof CD19-L1, CD19-L2, and CD19- L3 as set forth in Table 17.

838. The MBM of embodiment 807, wherein ABM3 comprises a heavy chainvariable region having the amino acid sequences of VHB as set forth inTable 17 and a light chain variable region having the amino acidsequences of VLB as set forth in Table 17.

839. The MBM of embodiment 807, wherein ABM3 comprises heavy chain CDRshaving the amino acid sequences of CD19-H1, CD19-H₂C, and CD19-H3 as setforth in Table 17 and light chain CDRs having the amino acid sequencesof CD19-L1, CD19-L2, and CD19- L3 as set forth in Table 17.

840. The MBM of embodiment 807, wherein ABM3 comprises a heavy chainvariable region having the amino acid sequences of VHC as set forth inTable 17 and a light chain variable region having the amino acidsequences of VLB as set forth in Table 2.

841. The MBM of embodiment 807, wherein ABM3 comprises heavy chain CDRshaving the amino acid sequences of CD19-H1, CD19-H₂D, and CD19-H3 as setforth in Table 17 and light chain CDRs having the amino acid sequencesof CD19-L1, CD19-L2, and CD19- L3 as set forth in Table 17.

842. The MBM of embodiment 807, wherein ABM3 comprises a heavy chainvariable region having the amino acid sequences of VHD as set forth inTable 17 and a light chain variable region having the amino acidsequences of VLB as set forth in Table 17.

843. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv1 as set forth in Table 17.

844. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv2 as set forth in Table 17.

845. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv3 as set forth in Table 17.

846. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv4 as set forth in Table 17.

847. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv5 as set forth in Table 17.

848. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv6 as set forth in Table 17.

849. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv7 as set forth in Table 17.

850. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv8 as set forth in Table 17.

851. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv9 as set forth in Table 17.

852. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv10 as set forth in Table 17.

853. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv11 as set forth in Table 17.

854. The MBM of embodiment 807, wherein ABM3 comprises a scFv comprisingthe amino acid sequence of CD19-scFv12 as set forth in Table 17.

855. The MBM of any one of embodiments 798 to 803, wherein ABM3comprises a binding sequence described in Table 16.

856. The MBM of embodiment 855, wherein ABM3 comprises the CDRs orvariable region sequences of the antibodies set forth in Table 16.

857. The MBM of any one of embodiments 1 to 856, which comprises a firstvariant Fc region and a second variant Fc region that together form anFc heterodimer.

858. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions S364K/E357Q : L368D/K370S.

859. The MBM of embodiments 857, wherein the first and second variant Fcregions comprise the amino acid substitutions L368D/K370S : S364K.

860. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions L368E/K370S : S364K.

861. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutionsT411T/E360E/Q362E : D401K.

862. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions L368D 370S : S364 /E357L.

863. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions 370S : S364K/E357Q.

864. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions of any one of the stericvariants listed in FIG. 4 of WO 2014/110601 (reproduced in Table 3).

865. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions of any one of the variantslisted in FIG. 5 of WO 2014/110601 (reproduced in Table 3).

866. The MBM of embodiment 857, wherein the first and second variant Fcregions comprise the amino acid substitutions of any one of the variantslisted in FIG. 6 of WO 2014/110601 (reproduced in Table 3).

867. The MBM of any one of embodiments 857 to 866, wherein at least oneof the Fc regions comprises an ablation variant modification.

868. The MBM of embodiment 867, wherein the ablation variantmodifications are selected from Table 2.

869. The MBM of embodiment 868, wherein the ablation variantmodification comprises G236R.

870.The MBM of embodiment 868, wherein the ablation variant modificationcomprises S239G.

871. The MBM of embodiment 868, wherein the ablation variantmodification comprises S239K.

872. The MBM of embodiment 868, wherein the ablation variantmodification comprises S239Q.

873. The MBM of embodiment 868, wherein the ablation variantmodification comprises S239R.

874. The MBM of embodiment 868, wherein the ablation variantmodification comprises V266D.

875. The MBM of embodiment 868, wherein the ablation variantmodification comprises S267K.

876. The MBM of embodiment 868, wherein the ablation variantmodification comprises S267R.

877. The MBM of embodiment 868, wherein the ablation variantmodification comprises H₂₆₈K.

878. The MBM of embodiment 868, wherein the ablation variantmodification comprises E269R.

879. The MBM of embodiment 868, wherein the ablation variantmodification comprises 299R.

880. The MBM of embodiment 868, wherein the ablation variantmodification comprises 299K 881. The MBM of embodiment 868, wherein theablation variant modification comprises K322A 882. The MBM of embodiment868, wherein the ablation variant modification comprises A327G 883. TheMBM of embodiment 868, wherein the ablation variant modificationcomprises A327L 884. The MBM of embodiment 868, wherein the ablationvariant modification comprises A327N 885. The MBM of embodiment 868,wherein the ablation variant modification comprises A327Q 886. The MBMof embodiment 868, wherein the ablation variant modification comprisesL328E 887. The MBM of embodiment 868, wherein the ablation variantmodification comprises L328R

888. The MBM of embodiment 868, wherein the ablation variantmodification comprises P329A

889. The MBM of embodiment 868, wherein the ablation variantmodification comprises P329H

890. The MBM of embodiment 868, wherein the ablation variantmodification comprises P329K

891. The MBM of embodiment 868, wherein the ablation variantmodification comprises A330L

892. The MBM of embodiment 868, wherein the ablation variantmodification comprises A330S/P331S

893. The MBM of embodiment 868, wherein the ablation variantmodification comprises 1332K

894. The MBM of embodiment 868, wherein the ablation variantmodification comprises 1332R

895. The MBM of embodiment 868, wherein the ablation variantmodification comprises V266D/A327Q

896. The MBM of embodiment 868, wherein the ablation variantmodification comprises V266D/P329K 897. The MBM of embodiment 868,wherein the ablation variant modification comprises G236R/L328R

898. The MBM of embodiment 868, wherein the ablation variantmodification comprises E233P/L234V/L235A/G236del/S239K.

899. The MBM of embodiment 868, wherein the ablation variantmodification comprises E233P/L234V/L235A/G236del/S267K.

900. The MBM of embodiment 868, wherein the ablation variantmodification comprises E233P/L234V/L235A/G236del/S239K/A327G.

901. The MBM of embodiment 868, wherein the ablation variantmodification comprises E233P/L234V/L235A/G236del/S267K/A327G.

902. The MBM of embodiment 868, wherein the ablation variantmodification comprises E233P/L234V/L235A/G236del.

903. The MBM of embodiment 868, wherein the ablation variantmodification comprises S239K/S267K.

904. The MBM of embodiment 868, wherein the ablation variantmodification comprises 267K/P329K.

905. The MBM of embodiment 868, wherein the ablation variantmodification comprises D265A/N297A/P329A.

906. The MBM of embodiment 868, wherein the ablation variantmodification comprises D265N/N297D/P329G.

907. The MBM of embodiment 868, wherein the ablation variantmodification comprises D265E/N297Q/P329S.

908. The MBM of any one of embodiments 867 to 907, wherein the Fc regioncomprising the ablation variant modification is operably linked to ABM1.

909. The MBM of any one of embodiments 867 to 907, wherein the Fc regioncomprising the ablation variant modification is operably linked to ABM2.

910. The MBM of any one of embodiments 867 to 907, wherein the Fc regioncomprising the ablation variant modification is operably linked to ABM3.

911. The MBM of any one of embodiments 867 to 907, wherein both variantFc regions comprise the ablation variant modification.

912. The MBM of any one of embodiments 857 to 911, wherein at least oneof the Fc regions further comprises pI variant substitutions.

913. The MBM of embodiment 912 wherein the pI variant substitutions areselected from Table 3.

914. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_ISO(-).

915. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(-)_isosteric_A.

916. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(-)_isosteric_B.

917. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in PLIS0(+RR).

918. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_ISO(+).

919. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(+)_isosteric_A.

920. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(+)_isosteric_B.

921. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(+)_isosteric_E269Q/E272Q.

922. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(+)_isosteric_E269Q/E283Q.

923. The MBM of embodiment 913, wherein the pI variant substitutionscomprise the substitutions present in pl_(+)_isosteric_E2720/E283Q.

924. The MBM of embodiment 913, wherein the p1 variant substitutionscomprise the substitutions present in pl_(+)_isosteric_E269Q.

925. The MBM of any one of embodiments 857 to 924, wherein the firstand/or second Fc region further comprises one or more amino acidsubstitution(s) selected from 434A, 434S, 428L, 308F, 2591, 428L, 434S,2591/308F, 4361/428L, 4361 or V, 434S, 436V, 428L, 252Y, 252Y, 254T,256E, 2591/308F, 428L, 236A, 239D, 239E, 332E, 332D, 239D, 332E, 267D,267E, 328F, 267E, 328F, 236A, 332E, 239D, 332E, 330Y, 239D, 332E, 330L,236R, 328R, 236R, 328R, 236N, 267E, 243L, 298A and 299T.

926. The MBM of any one of embodiments 857 to 924, wherein the firstand/or second Fc region further comprises the amino acid substitution434A, 434S or 434V.

927. The MBM of embodiment 926, wherein the first and/or second Fcregion further comprises the amino acid substitution 428L.

928. The MBM of any one of embodiments 926 to 927, wherein the firstand/or second Fc region further comprises the amino acid substitution308F.

929. The MBM of any one of embodiments 926 to 928, wherein the firstand/or second Fc region further comprises the amino acid substitution2591.

930. The MBM of any one of embodiments 926 to 929, wherein the firstand/or second Fc region further comprises the amino acid substitution4361.

931. The MBM of any one of embodiments 926 to 930, wherein the firstand/or second Fc region further comprises the amino acid substitution252Y.

932. The MBM of any one of embodiments 926 to 931, wherein the firstand/or second Fc region further comprises the amino acid substitution254T.

933. The MBM of any one of embodiments 926 to 932, wherein the firstand/or second Fc region further comprises the amino acid substitution256E.

934. The MBM of any one of embodiments 926 to 933, wherein the firstand/or second Fc region further comprises the amino acid substitution239D or 239E.

935. The MBM of any one of embodiments 926 to 934, wherein the firstand/or second Fc region further comprises the amino acid substitution332E or 332D.

936. The MBM of any one of embodiments 926 to 935, wherein the firstand/or second Fc region further comprises the amino acid substitution267D or 267E.

937. The MBM of any one of embodiments 926 to 936, wherein the firstand/or second Fc region further comprises the amino acid substitution330L.

938. The MBM of any one of embodiments 926 to 937, wherein the firstand/or second Fc region further comprises the amino acid substitution236R or 236N.

939. The MBM of any one of embodiments 926 to 938, wherein the firstand/or second Fc region further comprises the amino acid substitution328R.

940. The MBM of any one of embodiments 926 to 939, wherein the firstand/or second Fc region further comprises the amino acid substitution243L.

941. The MBM of any one of embodiments 926 to 940, wherein the firstand/or second Fc region further comprises the amino acid substitution298A.

942. The MBM of any one of embodiments 926 to 941, wherein the firstand/or second Fc region further comprises the amino acid substitution299T.

943. The MBM of embodiment 857, wherein:

-   -   (a) the first and second variant Fc regions comprise the amino        acid substitutions S364K/E357Q : L368D/K370S;    -   (b) the first and/or second variant Fc regions comprises the        ablation variant modifications E233P/L234V/L235A/G236del/S267K,        and    -   (c) the first and/or second variant Fc regions comprises the pI        variant substitutions N208D/Q295E/N384D/Q418E/N421D        (pl_(-)_isosteric_A).

944. The MBM of embodiment 943, wherein the first variant Fc regioncomprises the ablation variant modificationsE233P/L234V/L235A/G236del/S267K.

945. The MBM of any one of embodiments 943 to 944, wherein the secondvariant Fc region comprises the ablation variant modificationsE233P/L234V/L235A/G236del/S267K.

946. The MBM of any one of embodiments 943 to 945, wherein the firstvariant Fc region comprises the pI variant substitutionsN208D/Q295E/N384D/Q418E/N421D (pl_(-) _isosteric_A).

947. The MBM of any one of embodiments 943 to 946, wherein the secondvariant Fc region comprises the pI variant substitutionsN208D/Q295E/N384D/Q418E/N421D (pl_(-) _isosteric_A).

948. The MBM of any one of embodiments 857 to 947, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 90% identical to SEQ ID NO:869.

949. The MBM of any one of embodiments 857 to 947, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 95% identical to SEQ ID NO:869.

950. The MBM of any one of embodiments 857 to 947, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:869 modified with the substitutions recited in any one of embodiments858 to 947.

951. The MBM of any one of embodiments 857 to 947, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:869 with a substitution at 1, 2, 3, 4, 5 or 6 of positions 233, 234,235, 236, 237, 239, 265, 266, 267, 268, 269, 297, 299, 322, 327, 328,329, 330, 331 and 332, optionally wherein one or more of thesubstitutions are substitutions recited in any one of embodiments 858 to947.

952. The MBM of any one of 857 to 951, wherein the first or secondvariant Fc region comprises an amino acid sequence which is at least 90%identical to SEQ ID NO:870.

953. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 95% identical to SEQ ID NO:870.

954. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:870 modified with the substitutions recited in any one of embodiments858 to 947.

955. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:870 with a substitution at 1, 2, 3, 4, 5 or 6 of positions 233, 234,235, 236, 237, 239, 265, 266, 267, 268, 269, 297, 299, 322, 327, 328,329, 330, 331 and 332, optionally wherein one or more of thesubstitutions are substitutions recited in any one of embodiments 858 to947.

956. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 90% identical to SEQ ID NO:871.

957. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 95% identical to SEQ ID NO:871.

958. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:871 modified with the substitutions recited in any one of embodiments858 to 947.

959. The MBM of any one of embodiments 857 to 951, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:871 with a substitution at 1, 2, 3, 4, 5 or 6 of positions 233, 234,235, 236, 237, 239, 265, 266, 267, 268, 269, 297, 299, 322, 327, 328,329, 330, 331 and 332, optionally wherein one or more of thesubstitutions are substitutions recited in any one of embodiments 858 to947.

960. The MBM of any one of embodiments 857 to 959, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 90% identical to SEQ ID NO:872.

961. The MBM of any one of embodiments 857 to 959, wherein the first orsecond variant Fc region comprises an amino acid sequence which is atleast 95% identical to SEQ ID NO:872.

962. The MBM of any one of embodiments 857 to 959, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:872 modified with the substitutions recited in any one of embodiments858 to 947.

963. The MBM of any one of embodiments 857 to 959, wherein the first orsecond variant Fc region comprises the amino acid sequence of SEQ IDNO:872 with a substitution at 1, 2, 3, 4, 5 or 6 of positions 233, 234,235, 236, 237, 239, 265, 266, 267, 268, 269, 297, 299, 322, 327, 328,329, 330, 331 and 332, optionally wherein one or more of thesubstitutions are substitutions recited in any one of embodiments 858 to947.

964. The MBM of any one of embodiments 1 to 856 which comprises an Fcdomain.

965. The MBM of embodiment 964, wherein the Fc domain is an Fcheterodimer.

966. The MBM of embodiment 965, wherein the Fc heterodimer comprises anyof the Fc modifications set forth in Table 3.

967. The MBM of embodiment 965, wherein the Fc heterodimer comprisesknob-in- hole (“KIH”) modifications.

968. The MBM of embodiment 967, wherein the KIH modifications are any ofthe KIH modifications described in Section 7.3.1.5.1 or in Table 3.

969. The MBM of embodiment 967, wherein the KIH modifications are any ofthe alternative KIH modifications described in Section 7.3.1.5.2 or inTable 3.

970. The MBM of any one of embodiments 965 to 969, which comprises polarbridge modifications.

971. The MBM of embodiment 970, wherein the polar bridge modificationsare any of the polar bridge modifications described in Section 7.3.1.5.7or in Table 3.

972. The MBM of any one of embodiments to 965 to 971, which comprises atleast one of the Fc modifications designated as Fc 1 through Fc 150.

973. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 1 through Fc 5.

974. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 6 through Fc 10.

975. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 11 through Fc 15.

976. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 16 through Fc 20.

977. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 21 through Fc 25.

978. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 26 through Fc 30.

979. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 31 through Fc 35.

980. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 36 through Fc 40.

981. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 41 through Fc 45.

982. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 46 through Fc 50.

983. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 51 through Fc 55.

984. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 56 through Fc 60.

985. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 61 through Fc 65.

986. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 66 through Fc 70.

987. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 71 through Fc 75.

988. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 76 through Fc 80.

989. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 81 through Fc 85.

990. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 86 through Fc 90.

991. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 91 through Fc 95.

992. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 96 through Fc 100.

993. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 101 through Fc 105.

994. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 106 through Fc 110.

995. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 111 through Fc 115.

996. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 116 through Fc 120.

997. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 121 through Fc 125.

998. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 126 through Fc 130.

999. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 131 through Fc 135.

1000. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 136 through Fc 140.

1001. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 141 through Fc 145.

1002. The MBM of embodiment 972, which comprises at least one of the Fcmodifications designated as Fc 146 through Fc 150.

1003. The MBM of any one of embodiments 964 to 1002, wherein the Fcdomain has altered effector function.

1004. The MBM of embodiment 1003, wherein the Fc domain has alteredbinding to one or more Fc receptors.

1005. The MBM of embodiment 1004, wherein the one or more Fc receptorscomprise FcRN.

1006. The MBM of embodiment 1004 or embodiment 1005, wherein the one ormore Fc receptors comprise leukocyte receptors.

1007. The MBM of any one of embodiments 964 to 1006, wherein the Fc hasmodified disulfide bond architecture.

1008. The MBM of any one of embodiments 964 to 1007, wherein the Fc hasaltered glycosylation patterns.

1009. The MBM of any one of embodiments 964 to 1008, wherein the Fccomprises a hinge region.

1010. The MBM of embodiment 1009, wherein the hinge region comprises anyone of the hinge regions described in Section 7.3.2.

1011. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H1.

1012. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H_(2.)

1013. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H3.

1014. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H4.

1015. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H5.

1016. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H6.

1017. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H7.

1018. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H8.

1019. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H9.

1020. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H10.

1021. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H11.

1022. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H12.

1023. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H13.

1024. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H14.

1025. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H15.

1026. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H16.

1027. . The MBM of embodiment 1010, wherein the hinge region comprisesthe amino acid sequence of the hinge region designated H17.

1028. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H18.

1029. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H19.

1030. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H_(20.)

1031. The MBM of embodiment 1010, wherein the hinge region comprises theamino acid sequence of the hinge region designated H_(21.)

1032. The MBM of any one of embodiments 1 to 1031, which comprises atleast one scFv domain.

1033. The MBM of embodiment 1032, wherein at least one scFv comprises alinker connecting the VH and VL domains.

1034. The MBM of embodiment 1033, wherein the linker is 5 to 25 aminoacids in length.

1035. The MBM of embodiment 1034, wherein the linker is 12 to 20 aminoacids in length.

1036. The MBM of any one of embodiments 1033 to 1035, wherein the linkeris a charged linker and/or a flexible linker.

1037. The MBM of any one of embodiments 1033 to 1036, wherein the linkeris selected from any one of linkers L1 through L54.

1038. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L1.

1039. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L2.

1040. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L3.

1041. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L4.

1042. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L5.

1043. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L6.

1044. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L7.

1045. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L8.

1046. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L9.

1047. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L10.

1048. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L11.

1049. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L12.

1050. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L13.

1051. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L14.

1052. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L15.

1053. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L16.

1054. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L17.

1055. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L18.

1056. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L19.

1057. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L20.

1058. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L21.

1059. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L22.

1060. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L23.

1061. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L24.

1062. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L25.

1063. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L26.

1064. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L27.

1065. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L28.

1066. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L29.

1067. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L30.

1068. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L31.

1069. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L32.

1070. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L33.

1071. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L34.

1072. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L35.

1073. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L36.

1074. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L37.

1075. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L38.

1076. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L39.

1077. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L40.

1078. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L41.

1079. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L42.

1080. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L43.

1081. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L44.

1082. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L45.

1083. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L46.

1084. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L47.

1085. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L48.

1086. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L49.

1087. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L50.

1088. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L51.

1089. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L52.

1090. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L53.

1091. The MBM of embodiment 1037, wherein the linker region comprisesthe amino acid sequence of the linker designated L54.

1092. The MBM of any one of embodiments 1 to 1091, which comprises atleast one Fab domain.

1093. The MBM of embodiment 1092, wherein at least one Fab domaincomprises any of the Fab heterodimerization modifications set forth inTable 1.

1094. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F1.

1095. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F2.

1096. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F3.

1097. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F4.

1098. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F5.

1099. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F6.

1100. The MBM of embodiment 1093, wherein at least one Fab domaincomprises the Fab heterodimerization modifications designated as F7.

1101. The MBM of any one of embodiments 1 to 1100, which comprises atleast two ABMs, an ABM and an ABM chain, or two ABM chains connected toone another via a linker.

1102. The MBM of embodiment 1101, wherein the linker is 5 to 25 aminoacids in length.

1103. The MBM of embodiment 1102, wherein the linker is 12 to 20 aminoacids in length.

1104. The MBM of any one of embodiments 1101 to 1103, wherein the linkeris a charged linker and/or a flexible linker.

1105. The MBM of any one of embodiments 1101 to 1104, wherein the linkeris selected from any one of linkers L1 through L54.

1106. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L1.

1107. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L2.

1108. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L3.

1109. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L4.

1110. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L5.

1111. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L6.

1112. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L7.

1113. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L8.

1114. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L9.

1115. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L10.

1116. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L11.

1117. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L12.

1118. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L13.

1119. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L14.

1120. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L15.

1121. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L16.

1122. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L17.

1123. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L18.

1124. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L19.

1125. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L20.

1126. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L21.

1127. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L22.

1128. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L23.

1129. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L24.

1130. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L25.

1131. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L26.

1132. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L27.

1133. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L28.

1134. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L29.

1135. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L30.

1136. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L31.

1137. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L32.

1138. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L33.

1139. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L34.

1140. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L35.

1141. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L36.

1142. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L37.

1143. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L38.

1144. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L39.

1145. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L40.

1146. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L41.

1147. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L42.

1148. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L43.

1149. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L44.

1150. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L45.

1151. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L46.

1152. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L47.

1153. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L48.

1154. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L49.

1155. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L50.

1156. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L51.

1157. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L52.

1158. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L53.

1159. The MBM of embodiment 1105, wherein the linker region comprisesthe amino acid sequence of the linker designated L54.

1160. The MBM of any one of embodiments 1 to 1159, which is a trivalentMBM.

1161. The MBM of embodiment 1160, wherein the trivalent MBM has any oneof the configurations depicted in FIGS. 1B-1P.

1162. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1B.

1163. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 10 .

1164. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1D.

1165. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1E.

1166. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1F.

1167. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1G.

1168. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1H.

1169. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 11 .

1170. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1J.

1171. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1K.

1172. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1 L.

1173. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1M.

1174. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1N.

1175. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 10 .

1176. The MBM of embodiment 1161, wherein the trivalent MBM has theconfiguration depicted in FIG. 1P.

1177. The MBM of any one of embodiments 1161 to 1176, in which the ABMshave the configuration designated as T1.

1178. The MBM of any one of embodiments 1161 to 1176, in which the ABMshave the configuration designated as T2.

1179. The MBM of any one of embodiments 1161 to 1176, in which the ABMshave the configuration designated as T3.

1180. The MBM of any one of embodiments 1161 to 1176, in which the ABMshave the configuration designated as T4.

1181. The MBM of any one of embodiments 1161 to 1176, in which the ABMshave the configuration designated as T5.

1182. The MBM of any one of embodiments 1161 to 1176, in which the ABMshave the configuration designated as T6.

1183. The MBM of any one of embodiments 1 to 1159, which is atetravalent MBM. 1184. The MBM of embodiment 1183, wherein thetetravalent MBM has any one of the configurations depicted in FIGS.1Q-15.

1185. The MBM of embodiment 1184, wherein the tetravalent MBM has theconfiguration depicted in FIG. 1Q.

1186. The MBM of embodiment 1184, wherein the tetravalent MBM has theconfiguration depicted in FIG. 1R.

1187. The MBM of embodiment 1184, wherein the tetravalent MBM has theconfiguration depicted in FIG. 15 .

1188. The MBM of any one of embodiments 1184 to 1187, in which the ABMshave any of one the configurations designated Tv 1 through Tv 24.

1189. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 1.

1190. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 2.

1191. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 3.

1192. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 4.

1193. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 5.

1194. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 6.

1195. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 7.

1196. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 8.

1197. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 9.

1198. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 10.

1199. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 11.

1200. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 12.

1201. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 13.

1202. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 14.

1203. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 15.

1204. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 16.

1205. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 17.

1206. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 18.

1207. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 19.

1208. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 20.

1209. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 21.

1210. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 22.

1211. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 23.

1212. The MBM of embodiment 1188, in which the ABMs have theconfiguration designated Tv 24

1213. The MBM of any one of embodiments 1 to 1159, which is apentavalent MBM.

1214. The MBM of embodiment 1213, wherein the pentavalent MBM has theconfiguration depicted in FIG. 1T.

1215. The MBM of embodiment 1214, in which the ABMs have any one of theconfigurations designated Pv 1 through Pv 80.

1216. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 1 through Pv10.

1217. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 11 through Pv20.

1218. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 21 through Pv30.

1219. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 31 through Pv40.

1220. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 41 through Pv50.

1221. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 51 through Pv60.

1222. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 61 through Pv70.

1223. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 71 through Pv80.

1224. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 81 through Pv90.

1225. The MBM of embodiment 1215, in which the ABMs have a configurationselected from any one of the configurations designated Pv 91 through Pv100.

1226. The MBM of any one of embodiments 1 to 1159, which is a hexavalentMBM. 1227. The MBM of embodiment 1226, wherein the hexavalent MBM hasthe configuration depicted in FIG. 1U or FIG. 1V.

1228. The MBM of embodiment 1227, wherein the hexavalent MBM has theconfiguration depicted in FIG. 1U.

1229. The MBM of embodiment 1227, wherein the hexavalent MBM has theconfiguration depicted in FIG. 1V.

1230. The MBM of any one of embodiments 1227 to 1229, in which the ABMshave any one of the configurations designated Hv 1 through Hv 330.

1231. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 1 through Hv10.

1232. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 11 through Hv20.

1233. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 21 through Hv30.

1234. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 31 through Hv40.

1235. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 41 through Hv50.

1236. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 51 through Hv60.

1237. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 61 through Hv70.

1238. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 71 through Hv80.

1239. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 81 through Hv90.

1240. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 91 through Hv100.

1241. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 101 through Hv110.

1242. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 111 through Hv120.

1243. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 121 through Hv130.

1244. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 131 through Hv140.

1245. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 141 through Hv150.

1246. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 151 through Hv160.

1247. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 161 through Hv70.

1248. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 171 through Hv80.

1249. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 181 through Hv90.

1250. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 191 through Hv200.

1251. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 201 through Hv210.

1252. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 211 through Hv220.

1253. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 221 through Hv230.

1254. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 231 through Hv240.

1255. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 241 through Hv250.

1256. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 251 through Hv260.

1257. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 261 through Hv270.

1258. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 271 through Hv280.

1259. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 281 through Hv290.

1260. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 291 through Hv300.

1261. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 301 through Hv310.

1262. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 311 through Hv320.

1263. The MBM of embodiment 1230, in which the ABMs have a configurationselected from any one of the configurations designated Hv 321 through Hv330.

1264. The MBM of any one of embodiments 1 to 1263, wherein eachantigen-binding module is capable of binding its respective target atthe same time as each of the other antigen-binding modules is bound toits respective target.

1265. The MBM of any one of embodiments 1 to 1264, wherein any one, anytwo, or all three of ABM1, ABM2 and ABM3 has cross-species reactivity.

1266. The MBM of embodiment 1265, wherein ABM1 further bindsspecifically to BCMA in one or more non-human mammalian species.

1267. The MBM of embodiment 1265 or embodiment 1266, wherein ABM2further binds specifically to the component of a TCR complex in one ormore non-human mammalian species.

1268. The MBM of any one of embodiments 1264 to 1267, wherein ABM3further binds specifically to CD2 or the TAA in one or more non-humanmammalian species.

1269. The MBM of any one of embodiments 1265 to 1268, wherein the one ormore non-human mammalian species comprises one or more non-human primatespecies.

1270. The MBM of embodiment 1269, wherein the one or more non-humanprimate species comprises Macaca fascicularis.

1271. The MBM of embodiment 1269, wherein the one or more non-humanprimate species comprises Macaca mulatta.

1272. The MBM of embodiment 1269, wherein the one or more non-humanprimate species comprises Macaca nemestrina.

1273. The MBM of any one of embodiments 1265 to 1272, wherein the one ormore non-human mammalian species comprises Mus musculus.

1274. The MBM of any one of embodiments 1 to 1273, wherein any one, anytwo, or all three of ABM1, ABM2 and ABM3 does not have cross-speciesreactivity.

1275. The MBM of any one of embodiments 1 to 1274, which has beenrecombinantly produced, optionally in a mammalian host cell, which isoptionally selected from Vero cells, HeLa cells, COS cells, CHO cells,HEK293 cells, BHK cells and MDCKII cells.

1276. The MBM of any one of embodiments 1 to 1275, wherein the MBM is atrispecific binding molecule (TBM).

1277. The MBM of any one of embodiments 1 to 1276 for use as amedicament.

1278. The MBM of any one of embodiments 1 1276 for use in treating adisease or disorder associated with expression of BCMA.

1279. The MBM of embodiment 1278, wherein the disease or disordercomprises a cancer.

1280. The MBM of embodiment 1279, wherein the cancer comprises a B cellmalignancy.

1281. The MBM of embodiment 1280, wherein the B cell malignancy isselected from Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiplemyeloma.

1282. The MBM of embodiment 1279, wherein the cancer is Hodgkin'slymphoma.

1283. The MBM of embodiment 1282, wherein the Hodgkin's lymphoma isnodular sclerosing Hodgkin's lymphoma.

1284. The MBM of embodiment 1282, wherein the Hodgkin's lymphoma ismixed-cellularity subtype Hodgkin's lymphoma.

1285. The MBM of embodiment 1282, wherein the Hodgkin's lymphoma islymphocyte- rich or lymphocytic predominance Hodgkin's lymphoma.

1286. The MBM of embodiment 1282, wherein the Hodgkin's lymphoma islymphocyte depleted Hodgkin's lymphoma.

1287. The MBM of embodiment 1279, wherein the cancer is non-Hodgkin'slymphoma. 1288. The MBM of embodiment 1287, wherein the non-Hodgkin'slymphoma is a B cell lymphoma or a T cell lymphoma.

1289. The MBM of embodiment 1287, wherein the non-Hodgkin's lymphoma isa B cell lymphoma.

1290. The MBM of embodiment 1287, wherein the non-Hodgkin's lymphoma isdiffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chroniclymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle celllymphoma (MCL), marginal zone lymphoma, Burkitt lymphoma,lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia), hairy cellleukemia, primary central nervous system (CNS) lymphoma, primarymediastinal large B-cell lymphoma, mediastinal grey-zone lymphoma(MGZL), splenic marginal zone B-cell lymphoma, extranodal marginal zoneB-cell lymphoma of MALT, nodal marginal zone B-cell lymphoma, or primaryeffusion lymphoma.

1291. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isdiffuse large B-cell lymphoma (DLBCL).

1292. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isfollicular lymphoma.

1293. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma ischronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL).

1294. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma ismantle cell lymphoma (MCL).

1295. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma ismarginal zone lymphoma.

1296. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isBurkitt lymphoma.

1297. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma islymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia).

1298. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma ishairy cell leukemia.

1299. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isprimary central nervous system (CNS) lymphoma.

1300. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isprimary mediastinal large B-cell lymphoma.

1301. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma ismediastinal grey-zone lymphoma (MGZL).

1302. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma issplenic marginal zone B-cell lymphoma.

1303. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isextranodal marginal zone B-cell lymphoma of MALT.

1304. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isnodal marginal zone B-cell lymphoma.

1305. The MBM of embodiment 1290, wherein the non-Hodgkin's lymphoma isprimary effusion lymphoma.

1306. The MBM of embodiment 1287, wherein the non-Hodgkin's lymphoma isa T cell lymphoma.

1307. The MBM of embodiment 1306, wherein the non-Hodgkin's lymphoma isanaplastic large cell lymphoma (ALCL), adult T-cell lymphoma/leukemia,angiocentric lymphoma, angioimmunoblastic T-cell lymphoma, cutaneousT-cell lymphoma, extranodal natural killer/T-cell lymphoma, enteropathytype intestinal T-cell lymphoma, precursor T-lymphoblasticlymphoma/leukemia (T-LBL/L), or unspecified peripheral T-cell lymphoma.

1308. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isanaplastic large cell lymphoma (ALCL).

1309. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isadult T- cell lymphoma/leukemia.

1310. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isangiocentric lymphoma.

1311. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isangioimmunoblastic T-cell lymphoma.

1312. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma iscutaneous T-cell lymphoma.

1313. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isextranodal natural killer/T-cell lymphoma.

1314. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isenteropathy type intestinal T-cell lymphoma.

1315. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isprecursor T-lymphoblastic lymphoma/leukemia (T-LBL/L).

1316. The MBM of embodiment 1307, wherein the non-Hodgkin's lymphoma isunspecified peripheral T-cell lymphoma.

1317. The MBM of embodiment 1279, wherein the cancer is multiplemyeloma. 1318. The MBM of embodiment 1279, wherein the cancer is aplasmacytic dendritic cell neoplasm.

1319. The MBM of embodiment 1279, wherein the cancer comprises aleukemia.

1320. The MBM of embodiment 1319, wherein the leukemia is B-cell acutelymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”),acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML),chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia(B-CLL), B-cell prolymphocytic leukemia (B-PLL), hair cell leukemia,plasmacytoma/myeloma, precursor B-lymphoblastic leukemia/lymphoma(PB-LBL/L), large granular lymphocyte leukemia, precursorT-lymphoblastic lymphoma/leukemia (T-LBL/L), T-cell chronic lymphocyticleukemia/prolymphocytic leukemia (T-CLL/PLL).

1321. The MBM of embodiment 1320, wherein the leukemia is B-cell acutelymphoid leukemia (“BALL”).

1322. The MBM of embodiment 1320, wherein the leukemia is T-cell acutelymphoid leukemia (“TALL”).

1323. The MBM of embodiment 1320, wherein the leukemia is acute lymphoidleukemia (ALL).

1324. The MBM of embodiment 1320, wherein the leukemia is chronicmyelogenous leukemia (CML).

1325. The MBM of embodiment 1320, wherein the leukemia is chroniclymphocytic leukemia (CLL).

1326. The MBM of embodiment 1320, wherein the leukemia is B-cell chroniclymphocytic leukemia (B-CLL).

1327. The MBM of embodiment 1320, wherein the leukemia is B-cellprolymphocytic leukemia (B-PLL).

1328. The MBM of embodiment 1320, wherein the leukemia is hair cellleukemia. 1329. The MBM of embodiment 1320, wherein the leukemia isplasmacytoma/myeloma.

1330. The MBM of embodiment 1320, wherein the leukemia is precursor B-lymphoblastic leukemia/lymphoma (PB-LBL/L).

1331. The MBM of embodiment 1320, wherein the leukemia is large granularlymphocyte leukemia.

1332. The MBM of embodiment 1320, wherein the leukemia is precursor T-lymphoblastic lymphoma/leukemia (T-LBL/L).

1333. The MBM of embodiment 1320, wherein the leukemia is T-cell chroniclymphocytic leukemia/prolymphocytic leukemia (T-CLL/PLL).

1334. The MBM of embodiment 1279, wherein the cancer is a brain cancer.

1335. The MBM of embodiment 1334, wherein the brain cancer isastrocytoma or glioblastoma.

1336. The MBM of embodiment 1335, wherein the brain cancer isastrocytoma.

1337. The MBM of embodiment 1335, wherein the brain cancer isglioblastoma.

1338. The MBM of embodiment 1279, wherein the cancer is prostate cancer.

1339. The MBM of embodiment 1338, wherein the prostate cancer iscastrate-resistant prostate cancer.

1340. The MBM of embodiment 1338, wherein the prostate cancer istherapy-resistant prostate cancer.

1341. The MBM of embodiment 1338, wherein the prostate cancer ismetastatic prostate cancer.

1342. The MBM of embodiment 1279, wherein the cancer is pancreaticcancer.

1343. The MBM of embodiment 1279, wherein the cancer is lung cancer.

1344. The MBM of embodiment 1278, wherein the disease or disordercomprises a plasma cell neoplasm.

1345. The MBM of embodiment 1344, wherein plasma cell neoplasm comprisessmoldering multiple myeloma (SMM) or monoclonal gammopathy ofundetermined significance (MGUS).

1346. The MBM of embodiment 1345, wherein the plasma cell neoplasmcomprises smoldering multiple myeloma (SMM).

1347. The MBM of embodiment 1345, wherein the plasma cell neoplasmcomprises monoclonal gammopathy of undetermined significance (MGUS).

1348. The MBM of embodiment 1278, wherein the disease or disordercomprises a plasmacytoma.

1349. The MBM of embodiment 1348, wherein the plasmacytoma is plasmacell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullaryplasmacytoma, or multiple plasmacytoma.

1350. The MBM of embodiment 1348, wherein the plasmacytoma is plasmacell dyscrasia.

1351. The MBM of embodiment 1348, wherein the plasmacytoma is solitarymyeloma.

1352. The MBM of embodiment 1348, wherein the plasmacytoma is solitaryplasmacytoma.

1353. The MBM of embodiment 1348, wherein the plasmacytoma isextramedullary plasmacytoma.

1354. The MBM of embodiment 1348, wherein the plasmacytoma is multipleplasmacytoma.

1355. The MBM of embodiment 1278, wherein the disease or disordercomprises systemic amyloid light chain amyloidosis.

1356. The MBM of embodiment 1278, wherein the disease or disordercomprises POEMS syndrome.

1357. The MBM of embodiment 1278, wherein the disease or disorder is aninfection.

1358. The MBM of embodiment 1357, wherein the infection is a viralinfection.

1359. The MBM of embodiment 1358, wherein the viral infection is an HIVinfection.

1360. The MBM of embodiment 1357, wherein the infection is a fungalinfection.

1361. The MBM of embodiment 1360, wherein the fungal infection is a C.neoformans infection.

1362. The The MBM of embodiment 1278, wherein the disease or disorder isan autoimmune disorder.

1363. The MBM of embodiment 1362, wherein the autoimmune disorder isselected from systemic lupus erythematosus (SLE), Sjogren's syndrome,scleroderma, rheumatoid arthritis (RA), juvenile idiopathic arthritis,graft versus host disease, dermatomyositis, type I diabetes mellitus,Hashimoto's thyroiditis, Graves's disease, Addison's disease, celiacdisease, Crohn's Disease, pernicious anaemia, pemphigus vulgaris,vitiligo, autoimmune haemolytic anaemia, idiopathic thrombocytopenicpurpura, giant cell arteritis, myasthenia gravis, multiple sclerosis(MS) (e.g., relapsing-remitting MS (RRMS)), glomerulonephritis,Goodpasture's syndrome, bullous pemphigoid, colitis ulcerosa,Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy, anti-phospholipid syndrome, narcolepsy, sarcoidosis, andWegener's granulomatosis.

1364. The MBM of embodiment 1362, wherein the autoimmune disorder issystemic lupus erythematosus (SLE).

1365. The MBM of embodiment 1362, wherein the autoimmune disorder isSjogren's syndrome.

1366. The MBM of embodiment 1362, wherein the autoimmune disorder isscleroderma.

1367. The MBM of embodiment 1362, wherein the autoimmune disorder isrheumatoid arthritis (RA).

1368. The MBM of embodiment 1362, wherein the autoimmune disorder isjuvenile idiopathic arthritis.

1369. The MBM of embodiment 1362, wherein the autoimmune disorder isgraft versus host disease.

1370. The MBM of embodiment 1362, wherein the autoimmune disorder isdermatomyositis.

1371. The MBM of embodiment 1362, wherein the autoimmune disorder istype I diabetes mellitus.

1372. The MBM of embodiment 1362, wherein the autoimmune disorder isHashimoto's thyroiditis.

1373. The MBM of embodiment 1362, wherein the autoimmune disorder isGraves's disease.

1374. The MBM of embodiment 1362, wherein the autoimmune disorder isAddison's disease.

1375. The MBM of embodiment 1362, wherein the autoimmune disorder isceliac disease.

1376. The MBM of embodiment 1362, wherein the autoimmune disorder isCrohn's Disease.

1377. The MBM of embodiment 1362, wherein the autoimmune disorder ispernicious anaemia.

1378. The MBM of embodiment 1362, wherein the autoimmune disorder ispemphigus vulgaris.

1379. The MBM of embodiment 1362, wherein the autoimmune disorder isvitiligo.

1380. The MBM of embodiment 1362, wherein the autoimmune disorder isautoimmune haemolytic anaemia.

1381. The MBM of embodiment 1362, wherein the autoimmune disorder isidiopathic thrombocytopenic purpura.

1382. The MBM of embodiment 1362, wherein the autoimmune disorder isgiant cell arteritis.

1383. The MBM of embodiment 1362, wherein the autoimmune disorder ismyasthenia gravis.

1384. The MBM of embodiment 1362, wherein the autoimmune disorder ismultiple sclerosis (MS).

1385. The MBM of embodiment 1362, wherein the MS is relapsing-remittingMS (RRMS).

1386. The MBM of embodiment 1362, wherein the autoimmune disorder isglomerulonephritis.

1387. The MBM of embodiment 1362, wherein the autoimmune disorder isGoodpasture's syndrome.

1388. The MBM of embodiment 1362, wherein the autoimmune disorder isbullous pemphigoid.

1389. The MBM of embodiment 1362, wherein the autoimmune disorder iscolitis ulcerosa.

1390. The MBM of embodiment 1362, wherein the autoimmune disorder isGuillain-Barré syndrome.

1391. The MBM of embodiment 1362, wherein the autoimmune disorder ischronic inflammatory demyelinating polyneuropathy.

1392. The MBM of embodiment 1362, wherein the autoimmune disorder isanti-phospholipid syndrome.

1393. The MBM of embodiment 1362, wherein the autoimmune disorder isnarcolepsy.

1394. The MBM of embodiment 1362, wherein the autoimmune disorder issarcoidosis.

1395. The MBM of embodiment 1362, wherein the autoimmune disorder isWegener's granulomatosis.

1396. A conjugate comprising the MBM of any one of embodiments 1 to1276, and an agent, optionally a therapeutic agent, a diagnostic agent,a masking moiety, a cleavable moiety, or any combination thereof.

1397. The conjugate of embodiment 1396, wherein the agent is a cytotoxicor cytostatic agent.

1398. The conjugate of embodiment 1397, wherein the agent is any one ofthe agents described in Section 7.10.

1399. The conjugate of embodiment 1397 or 1398, wherein the agent is anyone of the agents described in Section 7.10.1.

1400. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a radionuclide.

1401. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to an alkylating agent.

1402. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a topoisomerase inhibitor, which is optionally atopoisomerase I inhibitor or a topoisomerase II inhibitor.

1403. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a DNA damaging agent.

1404. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a DNA intercalating agent, optionally a groovebinding agent such as a minor groove binding agent.

1405. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a RNA/DNA antimetabolite.

1406. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a kinase inhibitor.

1407. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a protein synthesis inhibitor.

1408. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a histone deacetylase (HDAC) inhibitor.

1409. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a mitochondrial inhibitor, which is optionally aninhibitor of a phosphoryl transfer reaction in mitochondria.

1410. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to an antimitotic agent.

1411. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a maytansinoid.

1412. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a kinesin inhibitor.

1413. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a kinesin-like protein KIF11 inhibitor.

1414. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a V-ATPase (vacuolar-type H+-ATPase) inhibitor.

1415. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a pro-apoptotic agent.

1416. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a Bcl2 (B-cell lymphoma 2) inhibitor.

1417. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to an MCL1 (myeloid cell leukemia 1) inhibitor.

1418. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a HSP90 (heat shock protein 90) inhibitor.

1419. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to an IAP (inhibitor of apoptosis) inhibitor.

1420. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to an mTOR (mechanistic target of rapamycin)inhibitor.

1421. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a microtubule stabilizer.

1422. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a microtubule destabilizer.

1423. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to an auristatin.

1424. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a dolastatin.

1425. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a MetAP (methionine aminopeptidase).

1426. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a CRM1 (chromosomal maintenance 1) inhibitor.

1427. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a DPPIV (dipeptidyl peptidase IV) inhibitor.

1428. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a proteasome inhibitor.

1429. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a protein synthesis inhibitor.

1430. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a CDK2 (cyclin-dependent kinase 2) inhibitor.

1431. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a CDK9 (cyclin-dependent kinase 9) inhibitor.

1432. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a RNA polymerase inhibitor.

1433. The conjugate of any one of embodiments 1396 to 1399, wherein theMBM is conjugated to a DHFR (dihydrofolate reductase) inhibitor.

1434. The conjugate of any one of embodiments 1396 to 1433, wherein theagent is attached to the MBM with a linker, which is optionally acleavable linker or a non-cleavable linker, e.g., a linker as describedin Section 7.10.2.

1435. The conjugate of any one of embodiments 1396 to 1434, wherein thecytotoxic or cytostatic agent is conjugated to the MBM via a linker asdescribed in Section 7.10.2.

1436. A preparation of MBMs comprising a plurality of MBMs moleculesaccording to any one of embodiments 1 to 1395 or a plurality ofconjugate molecules according to any one of embodiments 1396 to 1435,optionally wherein the plurality comprises at least 100, at least 1,000,at least 10,000, or at least 100,000 MBM molecules or conjugatemolecules.

1437. The preparation of embodiment 1436, wherein at least 50% of theMBM molecules in the preparation have the same primary amino acidsequence.

1438. The preparation of embodiment 1436, wherein at least 60% of theMBM molecules in the preparation have the same primary amino acidsequence.

1439. The preparation of embodiment 1436, wherein at least 70% of theMBM molecules in the preparation have the same primary amino acidsequence.

1440. The preparation of embodiment 1436, wherein at least 80% of theMBM molecules in the preparation have the same primary amino acidsequence.

1441. The preparation of embodiment 1436, wherein at least 90% of theMBM molecules in the preparation have the same primary amino acidsequence.

1442. The preparation of embodiment 1436, wherein at least 95% of theMBM molecules in the preparation have the same primary amino acidsequence.

1443. The preparation of embodiment 1436, wherein at least 97% of theMBM molecules in the preparation have the same primary amino acidsequence.

1444. The preparation of embodiment 1436, wherein at least 98% of theMBM molecules in the preparation have the same primary amino acidsequence.

1445. The preparation of embodiment 1436, wherein at least 99% of theMBM molecules in the preparation have the same primary amino acidsequence.

1446. The preparation of embodiment 1436, wherein 50% to 95% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1447. The preparation of embodiment 1436, wherein 50% to 80% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1448. The preparation of embodiment 1436, wherein 50% to 70% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1449. The preparation of embodiment 1436, wherein 60% to 95% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1450. The preparation of embodiment 1436, wherein 60% to 80% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1451. The preparation of embodiment 1436, wherein 60% to 70% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1452. The preparation of embodiment 1436, wherein 70% to 95% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1453. The preparation of embodiment 1436, wherein 70% to 80% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1454. The preparation of embodiment 1436, wherein 80% to 95% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1455. The preparation of embodiment 1436, wherein 95% to 99% of the MBMmolecules in the preparation have the same primary amino acid sequence.

1456. The preparation of any one of embodiments 1436 to 1455, wherein atleast 50% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1457. The preparation of any one of embodiments 1436 to 1455, wherein atleast 60% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1458. The preparation of any one of embodiments 1436 to 1455, wherein atleast 70% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1459. The preparation of any one of embodiments 1436 to 1455, wherein atleast 80% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1460. The preparation of any one of embodiments 1436 to 1455, wherein atleast 90% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1461. The preparation of any one of embodiments 1436 to 1455, wherein atleast 95% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1462. The preparation of any one of embodiments 1436 to 1455, wherein atleast 97% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1463. The preparation of any one of embodiments 1436 to 1455, wherein atleast 98% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1464. The preparation of any one of embodiments 1436 to 1455, wherein atleast 99% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1465. The preparation of any one of embodiments 1436 to 1455, wherein50% to 95% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1466. The preparation of any one of embodiments 1436 to 1455, wherein50% to 80% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1467. The preparation of any one of embodiments 1436 to 1455, wherein50% to 70% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1468. The preparation of any one of embodiments 1436 to 1455, wherein60% to 95% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1469. The preparation of any one of embodiments 1436 to 1455, wherein60% to 80% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1470. The preparation of any one of embodiments 1436 to 1455, wherein60% to 70% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1471. The preparation of any one of embodiments 1436 to 1455, wherein70% to 95% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1472. The preparation of any one of embodiments 1436 to 1455, wherein70% to 80% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1473. The preparation of any one of embodiments 1436 to 1455, wherein80% to 95% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1474. The preparation of any one of embodiments 1436 to 1455, wherein95% to 99% of the MBM molecules in the preparation have the sameinterchain crosslinks.

1475. The preparation of any one of embodiments 1436 to 1474, wherein atleast 50% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1476. The preparation of any one of embodiments 1436 to 1474, wherein atleast 60% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1477. The preparation of any one of embodiments 1436 to 1474, wherein atleast 70% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1478. The preparation of any one of embodiments 1436 to 1474, wherein atleast 80% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1479. The preparation of any one of embodiments 1436 to 1474, wherein atleast 90% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1480. The preparation of any one of embodiments 1436 to 1474, wherein atleast 95% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1481. The preparation of any one of embodiments 1436 to 1474, wherein atleast 97% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1482. The preparation of any one of embodiments 1436 to 1474, wherein atleast 98% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1483. The preparation of any one of embodiments 1436 to 1474, wherein atleast 99% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1484. The preparation of any one of embodiments 1436 to 1474, wherein50% to 95% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1485. The preparation of any one of embodiments 1436 to 1474, wherein50% to 80% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1486. The preparation of any one of embodiments 1436 to 1474, wherein50% to 70% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1487. The preparation of any one of embodiments 1436 to 1474, wherein60% to 95% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1488. The preparation of any one of embodiments 1436 to 1474, wherein60% to 80% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1489. The preparation of any one of embodiments 1436 to 1474, wherein60% to 70% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1490. The preparation of any one of embodiments 1436 to 1474, wherein70% to 95% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1491. The preparation of any one of embodiments 1436 to 1474, wherein70% to 80% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1492. The preparation of any one of embodiments 1436 to 1474, wherein80% to 95% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1493. The preparation of any one of embodiments 1436 to 1474, wherein95% to 99% of the MBM molecules in the preparation have the sameABM1:ABM2:ABM3 ratio.

1494. A pharmaceutical composition comprising the MBM of any one ofembodiments 1 to 1276, the conjugate of any one of embodiments 1396 to1435, or the preparation of any one of embodiments 1436 to 1493, and anexcipient.

1495. A method of treating a subject having a disease or disorderassociated with expression of BCMA, comprising administering to asubject an effective amount of the MBM of any one of embodiments 1 to1395, the conjugate of any one of embodiments 1396 to 1435, thepreparation of any one of embodiments 1436 to 1493, or thepharmaceutical composition of embodiment 1494.

1496. The method of embodiment 1495, wherein the disease or disordercomprises a cancer.

1497. The method of embodiment 1496, wherein the cancer comprises a Bcell malignancy.

1498. The method of embodiment 1497, wherein when the MBM is a MBM thatbinds specifically to a TAA, the B cell malignancy comprises cancerous Bcells expressing both BCMA and the TAA.

1499. The method of embodiment 1497, wherein when the MBM is a MBM thatbinds specifically to a TAA, the B cell malignancy comprises cancerous Bcells expressing BCMA, but not the TAA, and cancerous B cells expressingthe TAA, but not BCMA.

1500. The method of any one of embodiments 1497 to 1499, wherein the Bcell malignancy is selected from selected from Hodgkin's lymphoma,non-Hodgkin's lymphoma and multiple myeloma.

1501. The method of embodiment 1496, wherein the cancer is Hodgkin'slymphoma.

1502. The method of embodiment 1501, wherein the Hodgkin's lymphoma isnodular sclerosing Hodgkin's lymphoma.

1503. The method of embodiment 1501, wherein the Hodgkin's lymphoma ismixed- cellularity subtype Hodgkin's lymphoma.

1504. The method of embodiment 1501, wherein the Hodgkin's lymphoma islymphocyte-rich or lymphocytic predominance Hodgkin's lymphoma.

1505. The method of embodiment 1501, wherein the Hodgkin's lymphoma islymphocyte depleted Hodgkin's lymphoma.

1506. The method of embodiment 1496, wherein the cancer is non-Hodgkin'slymphoma.

1507. The method of embodiment 1506, wherein the non-Hodgkin's lymphomais a B cell lymphoma or a T cell lymphoma.

1508. The method of embodiment 1507, wherein the non-Hodgkin's lymphomais a B cell lymphoma.

1509. The method of embodiment 1508, wherein the non-Hodgkin's lymphomais diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chroniclymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL), mantlecell lymphoma (MCL), marginal zone lymphoma, Burkitt lymphoma,lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia), hairy cellleukemia, primary central nervous system (CNS) lymphoma, primarymediastinal large B-cell lymphoma, mediastinal grey-zone lymphoma(MGZL), splenic marginal zone B-cell lymphoma, extranodal marginal zoneB-cell lymphoma of MALT, nodal marginal zone B-cell lymphoma, or primaryeffusion lymphoma.

1510. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais diffuse large B-cell lymphoma (DLBCL).

1511. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais follicular lymphoma.

1512. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL).

1513. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais mantle cell lymphoma (MCL).

1514. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais marginal zone lymphoma.

1515. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais Burkitt lymphoma.

1516. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia).

1517. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais hairy cell leukemia.

1518. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais primary central nervous system (CNS) lymphoma.

1519. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais primary mediastinal large B-cell lymphoma.

1520. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais mediastinal grey-zone lymphoma (MGZL).

1521. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais splenic marginal zone B-cell lymphoma.

1522. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais extranodal marginal zone B-cell lymphoma of MALT.

1523. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais nodal marginal zone B-cell lymphoma.

1524. The method of embodiment 1509, wherein the non-Hodgkin's lymphomais primary effusion lymphoma.

1525. The method of embodiment 1507, wherein the non-Hodgkin's lymphomais a T cell lymphoma.

1526. The method of embodiment 1525, wherein the non-Hodgkin's lymphomais anaplastic large cell lymphoma (ALCL), adult T-celllymphoma/leukemia, angiocentric lymphoma, angioimmunoblastic T-celllymphoma, cutaneous T-cell lymphoma, extranodal natural killer/T-celllymphoma, enteropathy type intestinal T-cell lymphoma, precursorT-lymphoblastic lymphoma/leukemia (T-LBL/L), or unspecified peripheralT-cell lymphoma.

1527. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais anaplastic large cell lymphoma (ALCL).

1528. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais adult T-cell lymphoma/leukemia.

1529. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais angiocentric lymphoma.

1530. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais angioimmunoblastic T-cell lymphoma.

1531. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais cutaneous T-cell lymphoma.

1532. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais extranodal natural killer/T-cell lymphoma.

1533. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais enteropathy type intestinal T-cell lymphoma.

1534. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais precursor T-lymphoblastic lymphoma/leukemia (T-LBL/L).

1535. The method of embodiment 1526, wherein the non-Hodgkin's lymphomais unspecified peripheral T-cell lymphoma.

1536. The method of embodiment 1496, wherein the cancer is multiplemyeloma.

1537. The method of embodiment 1496, wherein the cancer is a plasmacyticdendritic cell neoplasm.

1538. The method of embodiment 1496, wherein the cancer comprises aleukemia.

1539. The method of embodiment 1538, wherein the leukemia is B-cellacute lymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia(“TALL”), acute lymphoid leukemia (ALL), chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocyticleukemia (B-CLL), B-cell prolymphocytic leukemia (B-PLL), hair cellleukemia, plasmacytoma/myeloma, precursor B-lymphoblasticleukemia/lymphoma (PB-LBL/L), large granular lymphocyte leukemia,precursor T-lymphoblastic lymphoma/leukemia (T-LBL/L), T-cell chroniclymphocytic leukemia/prolymphocytic leukemia (T-CLL/PLL).

1540. The method of embodiment 1538, wherein the leukemia is B-cellacute lymphoid leukemia (“BALL”).

1541. The method of embodiment 1538, wherein the leukemia is T-cellacute lymphoid leukemia (“TALL”).

1542. The method of embodiment 1538, wherein the leukemia is acutelymphoid leukemia (ALL).

1543. The method of embodiment 1538, wherein the leukemia is chronicmyelogenous leukemia (CML).

1544. The method of embodiment 1538, wherein the leukemia is chroniclymphocytic leukemia (CLL).

1545. The method of embodiment 1538, wherein the leukemia is B-cellchronic lymphocytic leukemia (B-CLL).

1546. The method of embodiment 1538, wherein the leukemia is B-cellprolymphocytic leukemia (B-PLL).

1547. The method of embodiment 1538, wherein the leukemia is hair cellleukemia. 1548. The method of embodiment 1538, wherein the leukemia isplasmacytoma/myeloma.

1549. The method of embodiment 1538, wherein the leukemia is precursorB- lymphoblastic leukemia/lymphoma (PB-LBL/L).

1550. The method of embodiment 1538, wherein the leukemia is largegranular lymphocyte leukemia.

1551. The method of embodiment 1538, wherein the leukemia is precursorT- lymphoblastic lymphoma/leukemia (T-LBL/L).

1552. The method of embodiment 1538, wherein the leukemia is T-cellchronic lymphocytic leukemia/prolymphocytic leukemia (T-CLL/PLL).

1553. The method of embodiment 1496, wherein the cancer is a braincancer. 1554. The method of embodiment 1553, wherein the brain cancer isastrocytoma or glioblastoma.

1555. The method of embodiment 1554, wherein the brain cancer isastrocytoma.

1556. The method of embodiment 1554, wherein the brain cancer isglioblastoma.

1557. The method of embodiment 1496, wherein the cancer is prostatecancer.

1558. The method of embodiment 1557, wherein the prostate cancer iscastrate- resistant prostate cancer.

1559. The method of embodiment 1557, wherein the prostate cancer istherapy- resistant prostate cancer.

1560. The method of embodiment 1557, wherein the prostate cancer ismetastatic prostate cancer.

1561. The method of embodiment 1496, wherein the cancer is pancreaticcancer.

1562. The method of embodiment 1496, wherein the cancer is lung cancer.

1563. The method of embodiment 1496, wherein the disease or disordercomprises a plasma cell neoplasm.

1564. The method of embodiment 1563, wherein plasma cell neoplasmcomprises smoldering multiple myeloma (SMM) or monoclonal gammopathy ofundetermined significance (MGUS).

1565. The method of embodiment 1564, wherein the plasma cell neoplasmcomprises smoldering multiple myeloma (SMM).

1566. The method of embodiment 1564, wherein the plasma cell neoplasmcomprises monoclonal gammopathy of undetermined significance (MGUS).

1567. The method of embodiment 1495, wherein the disease or disordercomprises a plasmacytoma.

1568. The method of embodiment 1567, wherein the plasmacytoma is plasmacell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullaryplasmacytoma, or multiple plasmacytoma.

1569. The method of embodiment 1567, wherein the plasmacytoma is plasmacell dyscrasia.

1570. The method of embodiment 1567, wherein the plasmacytoma issolitary myeloma.

1571. The method of embodiment 1567, wherein the plasmacytoma issolitary plasmacytoma.

1572. The method of embodiment 1567, wherein the plasmacytoma isextramedullary plasmacytoma.

1573. The method of embodiment 1567, wherein the plasmacytoma ismultiple plasmacytoma.

1574. The method of embodiment 1495, wherein the disease or disordercomprises systemic amyloid light chain amyloidosis.

1575. The method of embodiment 1495, wherein the disease or disordercomprises POEMS syndrome.

1576. The method of any one of embodiments 1495 to 1537, furthercomprising administering at least one additional agent to the subject.

1577. The method of embodiment 1576, wherein the additional agent is achemotherapeutic agent.

1578. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an anthracycline.

1579. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a vinca alkaloid.

1580. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an alkylating agent.

1581. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an immune cell antibody.

1582. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an antimetabolite.

1583. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an adenosine deaminase inhibitor

1584. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an mTOR inhibitor.

1585. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a TNFR glucocorticoid induced TNFR related protein(GITR) agonist.

1586. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a proteasome inhibitor.

1587. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a BH3 mimetic.

1588. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a cytokine.

1589. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent prevents or slows shedding of BCMA from a cancer celland/or, when the MBM binds specifically to a TAA, the TAA from a cancercell.

1590. The method of embodiment 1589, wherein the additional agentcomprises an ADAM10 inhibitor and/or an ADAM 17 inhibitor.

1591. The method of embodiment 1589, wherein the additional agentcomprises a phospholipase inhibitor.

1592. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a gamma secretase inhibitor.

1593. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an immunomodulatory.

1594. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a thalidomide derivative.

1595. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an EGFR inhibitor.

1596. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an adenosine A2A receptor antagonist.

1597. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a CD20 inhibitor.

1598. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a CD22 inhibitor.

1599. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a FCRL2 inhibitor.

1600. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a FCRLS inhibitor.

1601. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a IL-15/IL15-Ra complex.

1602. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a PD-1 inhibitor.

1603. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a PD-L1 inhibitor.

1604. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a LAG-3 inhibitor.

1605. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a TIM-3 inhibitor.

1606. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a TGF-13 inhibitor.

1607. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a CD73 inhibitor.

1608. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a IL-17 inhibitor.

1609. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is a CD32B inhibitor

1610. The method of embodiment 1576 or embodiment 1577, wherein theadditional agent is an agent selected from those listed in Table 18.

1611. The method of embodiment 1576, wherein the additional agent is anagent that reduces or ameliorates a side effect associated with theadministration of a MBM that binds CD3.

1612. The method of embodiment 1611, wherein the additional agentcomprises a steroid (e.g., corticosteroid), an inhibitor of TNFα (e.g.,an anti-TNFα antibody molecule such as infliximab, adalimumab,certolizumab pegol, or golimumab, a fusion protein such as entanercept,a small molecule inhibitor of TNFα such as a xanthine derivative (e.g.pentoxifylline) or bupropion), an IL-6 inhibitor (e.g., an IL-6 antibodymolecule such as tocilizumab (toc), sarilumab, elsilimomab, ONTO 328,ALD518/BMS-945429, ONTO 136, CPSI-

2364, CDP6038, VX₃₀, AR^(G) X-109, FE301, or FM101), an IL-1R basedinhibitor such as anakinra, a corticosteroid (e.g., methylprednisoloneor hydrocortisone) in combination with Benadryl and Tylenol, avasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine,vasopressin, or any combination thereof), an antipyretic agent, or ananalgesic agent.

1613. The method of any one of embodiments 1576 to 1612, wherein theadditional agent is not an antibody.

1614. The method of embodiment 1495, wherein the disease or disorder isan infection.

1615. The method of embodiment 1614, wherein the infection is a viralinfection.

1616. The method of embodiment 1615, wherein the viral infection is anHIV infection.

1617. The method of embodiment 1614, wherein the infection is a fungalinfection.

1618. The method of embodiment 1617, wherein the fungal infection is aC. neoformans infection.

1619. The method of embodiment 1495, wherein the disease or disorder isan autoimmune disorder.

1620. The method of embodiment 1619, wherein the autoimmune disorder isselected from systemic lupus erythematosus (SLE), Sjogren's syndrome,scleroderma, rheumatoid arthritis (RA), juvenile idiopathic arthritis,graft versus host disease, dermatomyositis, type I diabetes mellitus,Hashimoto's thyroiditis, Graves's disease, Addison's disease, celiacdisease, Crohn's Disease, pernicious anaemia, pemphigus vulgaris,vitiligo, autoimmune haemolytic anaemia, idiopathic thrombocytopenicpurpura, giant cell arteritis, myasthenia gravis, multiple sclerosis(MS) (e.g., relapsing-remitting MS (RRMS)), glomerulonephritis,Goodpasture's syndrome, bullous pemphigoid, colitis ulcerosa,Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy, anti-phospholipid syndrome, narcolepsy, sarcoidosis, andWegener's granulomatosis.

1621. The method of embodiment 1620, wherein the autoimmune disorder issystemic lupus erythematosus (SLE).

1622. The method of embodiment 1620, wherein the autoimmune disorder isSjogren's syndrome.

1623. The method of embodiment 1620, wherein the autoimmune disorder isscleroderma.

1624. The method of embodiment 1620, wherein the autoimmune disorder isrheumatoid arthritis (RA).

1625. The method of embodiment 1620, wherein the autoimmune disorder isjuvenile idiopathic arthritis.

1626. The method of embodiment 1620, wherein the autoimmune disorder isgraft versus host disease.

1627. The method of embodiment 1620, wherein the autoimmune disorder isdermatomyositis.

1628. The method of embodiment 1620, wherein the autoimmune disorder istype I diabetes mellitus.

1629. The method of embodiment 1620, wherein the autoimmune disorder isHashimoto's thyroiditis.

1630. The method of embodiment 1620, wherein the autoimmune disorder isGraves's disease.

1631. The method of embodiment 1620, wherein the autoimmune disorder isAddison's disease.

1632. The method of embodiment 1620, wherein the autoimmune disorder isceliac disease.

1633. The method of embodiment 1620, wherein the autoimmune disorder isCrohn's Disease.

1634. The method of embodiment 1620, wherein the autoimmune disorder ispernicious anaemia.

1635. The method of embodiment 1620, wherein the autoimmune disorder ispemphigus vulgaris.

1636. The method of embodiment 1620, wherein the autoimmune disorder isvitiligo.

1637. The method of embodiment 1620, wherein the autoimmune disorder isautoimmune haemolytic anaemia.

1638. The method of embodiment 1620, wherein the autoimmune disorder isidiopathic thrombocytopenic purpura.

1639. The method of embodiment 1620, wherein the autoimmune disorder isgiant cell arteritis.

1640. The method of embodiment 1620, wherein the autoimmune disorder ismyasthenia gravis.

1641. The method of embodiment 1620, wherein the autoimmune disorder ismultiple sclerosis (MS).

1642. The method of embodiment 1641, wherein the MS isrelapsing-remitting MS (RRMS).

1643. The method of embodiment 1620, wherein the autoimmune disorder isglomerulonephritis.

1644. The method of embodiment 1620, wherein the autoimmune disorder isGoodpasture's syndrome.

1645. The method of embodiment 1620, wherein the autoimmune disorder isbullous pemphigoid.

1646. The method of embodiment 1620, wherein the autoimmune disorder iscolitis ulcerosa.

1647. The method of embodiment 1620, wherein the autoimmune disorder isGuillain- Barré syndrome.

1648. The method of embodiment 1620, wherein the autoimmune disorder ischronic inflammatory demyelinating polyneuropathy.

1649. The method of embodiment 1620, wherein the autoimmune disorder isanti- phospholipid syndrome.

1650. The method of embodiment 1620, wherein the autoimmune disorder isnarcolepsy.

1651. The method of embodiment 1620, wherein the autoimmune disorder issarcoidosis.

1652. The method of embodiment 1620, wherein the autoimmune disorder isWegener's granulomatosis.

1653. A nucleic acid or plurality of nucleic acids encoding the MBM ofany one of embodiments 1 to 1395.

1654. The nucleic acid or plurality of nucleic acids of embodiment 1653which is a DNA (are DNAs).

1655. The nucleic acid or plurality of nucleic acids of embodiment 1654which are in the form of one or more vectors, optionally expressionvectors.

1656. The nucleic acid or plurality of nucleic acids of embodiment 1653which is a mRNA (are mRNAs).

1657. A cell engineered to express the MBM of any one of embodiments 1to 1395.

1658. A cell transfected with one or more expression vectors comprisingone or more nucleic acid sequences encoding the MBM of any one ofembodiments 1 to 1395 under the control of one or more promoters.

1659. The cell of embodiment 1657 or embodiment 1658, wherein expressionof the MBM is under the control of one or more inducible promoters.

1660. The cell of any one of embodiments 1657 to 1659, wherein the MBMis produced in secretable form.

1661. A method of producing a MBM, comprising:

-   -   (a) culturing the cell of any one of embodiments 1657 to 1660 in        conditions under which the MBM is expressed; and    -   (b) recovering the MBM from the cell culture.

10. INCORPORATION BY REFERENCE

All publications, patents, patent applications and other documents citedin this application are hereby incorporated by reference in theirentireties for all purposes to the same extent as if each individualpublication, patent, patent application or other document wereindividually indicated to be incorporated by reference for all purposes.In the event that there are any inconsistencies between the teachings ofone or more of the references incorporated herein and the presentdisclosure, the teachings of the present specification are intended.

What is claimed is:
 1. A multispecific binding molecule (MBM),comprising: (a) an antigen-binding module 1 (ABM1) that bindsspecifically to human BCMA and comprises CDR-L1, CDR-L2 and CDR-L3sequences set forth in Table 11A-1, Table 11B-1, Table 11C-1, Table11D-1, Table 11E-1, Table 11F-1, Table 11G-1, Table 11H-1, Table 11I-1,Table 11J-1, Table 11K-1(a), Table 11K-1(b), Table 11L-1, Table 11M-1,Table 11N-1(a), or Table 11N-1(b), and the corresponding CDR-H1, CDR-H2and CDR-H3 sequence set forth in Table 11A-2, Table 11B-2, Table 11C-2,Table 11D-2, Table 11E-2, Table 11F-2, Table 11G-2, Table 11H-2, Table11I-2, Table 11J-2, Table 11K-2, Table 11K-2, Table 11L-2, Table 11M-2,Table 11N-2, or Table 11N-2, respectively; (b) an antigen-binding module2 (ABM2) that binds specifically to a component of a human T-cellreceptor (TCR) complex; and (c) an antigen-binding module 3 (ABM3) thatbinds specifically to human CD2 or a human tumor-associated antigen(TAA).
 2. The MBM of claim 1, wherein ABM1 comprises CDR-L1, CDR-L2 andCDR-L3 sequences set forth in Table 11A-1, Table 11B-1, Table 11C-1,Table 11D-1, Table 11E-1, Table 11F-1, Table 11G-1, Table 11H-1, Table11I-1, Table 11J-1, Table 11K-1(a), Table 11L-1, Table 11M-1, or Table11N-1(a), and the corresponding CDR-H1, CDR-H2 and CDR-H3 sequence setforth in Table 11A-2, Table 11B-2, Table 11C-2, Table 11D-2, Table11E-2, Table 11F-2, Table 11G-2, Table 11H-2, Table 11I-2, Table 11J-2,Table 11K-2, Table 11L-2, Table 11M-2, or Table 11N-2, respectively. 3.The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1, CDR-L2 andCDR-L3 sequences set forth in Table 11A-1 and the corresponding CDR-H1,CDR-H2 and CDR-H3 sequence set forth in Table 11A-2.
 4. The MBM of claim1 or claim 2, wherein ABM1 comprises CDR-L1, CDR-L2 and CDR-L3 sequencesset forth in Table 11B-1 and the corresponding CDR-H1, CDR-H2 and CDR-H3sequence set forth in Table 11B-2.
 5. The MBM of claim 1 or claim 2,wherein ABM1 comprises CDR-L1, CDR-L2 and CDR-L3 sequences set forth inTable 11C-1 and the corresponding CDR-H1, CDR-H2 and CDR-H3 sequence setforth in Table 11C-2.
 6. The MBM of claim 1 or claim 2, wherein ABM1comprises CDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11D-1and the corresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth inTable 11D-2.
 7. The MBM of claim 1 or claim 2, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11E-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11E-2.
 8. The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1,CDR-L2 and CDR-L3 sequences set forth in Table 11F-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11F-2.
 9. The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1,CDR-L2 and CDR-L3 sequences set forth in Table 11G-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11G-2.
 10. The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1,CDR-L2 and CDR-L3 sequences set forth in Table 11H-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11H-2.
 11. The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1,CDR-L2 and CDR-L3 sequences set forth in Table 11I-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11I-2.
 12. The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1,CDR-L2 and CDR-L3 sequences set forth in Table 11J-1 and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11J-2.
 13. The MBM of claim 1 or claim 2, wherein ABM1 comprises CDR-L1,CDR-L2 and CDR-L3 sequences set forth in Table 11K-1(a) and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11K-2.
 14. The MBM of claim 1, wherein ABM1 comprises CDR-L1, CDR-L2 andCDR-L3 sequences set forth in Table 11K-1(b) and the correspondingCDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table 11K-2.
 15. The MBMof claim 1 or claim 2, wherein ABM1 comprises CDR-L1, CDR-L2 and CDR-L3sequences set forth in Table 11L-1 and the corresponding CDR-H1, CDR-H2and CDR-H3 sequence set forth in Table 11L-2.
 16. The MBM of claim 1 orclaim 2, wherein ABM1 comprises CDR-L1, CDR-L2 and CDR-L3 sequences setforth in Table 11M-1 and the corresponding CDR-H1, CDR-H2 and CDR-H3sequence set forth in Table 11M-2.
 17. The MBM of claim 1 or claim 2,wherein ABM1 comprises CDR-L1, CDR-L2 and CDR-L3 sequences set forth inTable 11N-1(a) and the corresponding CDR-H1, CDR-H2 and CDR-H3 sequenceset forth in Table 11N-2.
 18. The MBM of claim 1, wherein ABM1 comprisesCDR-L1, CDR-L2 and CDR-L3 sequences set forth in Table 11N-1(b) and thecorresponding CDR-H1, CDR-H2 and CDR-H3 sequence set forth in Table11N-2.
 19. The MBM of claim 3, wherein the CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences are those of C1.
 20. The MBM ofclaim 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3sequences are those of C2.
 21. The MBM of claim 3, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of C3. 22.The MBM of claim 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2and CDR-H3 sequences are those of C4.
 23. The MBM of claim 3, whereinthe CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences arethose of C5.
 24. The MBM of claim 3, wherein the CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences are those of C6.
 25. The MBM ofclaim 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3sequences are those of C7.
 26. The MBM of claim 3, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of C8. 27.The MBM of claim 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2and CDR-H3 sequences are those of C9.
 28. The MBM of claim 3, whereinthe CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences arethose of C10.
 29. The MBM of claim 3, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of C11.
 30. TheMBM of claim 3, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of C12.
 31. The MBM of claim 4, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofC13.
 32. The MBM of claim 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C14.
 33. The MBM of claim 4,wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequencesare those of C15.
 34. The MBM of claim 4, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of C16.
 35. TheMBM of claim 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of C17.
 36. The MBM of claim 4, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofC18.
 37. The MBM of claim 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C19.
 38. The MBM of claim 4,wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequencesare those of C20.
 39. The MBM of claim 4, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of C21.
 40. TheMBM of claim 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of C22.
 41. The MBM of claim 4, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofC23.
 42. The MBM of claim 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of C24.
 43. The MBM of claim 4,wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequencesare those of C25.
 44. The MBM of claim 4, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of C26.
 45. TheMBM of claim 4, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of C27.
 46. The MBM of claim 4, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofC28.
 47. The MBM of any one of claims 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of AB1.48. The MBM of any one of claims 5 to 10, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of AB2.
 49. TheMBM of any one of claims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences are those of R1F2.
 50. The MBM ofany one of claims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of PALF03.
 51. The MBM of any oneof claims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2and CDR-H3 sequences are those of PALF04.
 52. The MBM of any one ofclaims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of PALF05.
 53. The MBM of any one of claims 5to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3sequences are those of PALF06.
 54. The MBM of any one of claims 5 to 10,wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequencesare those of PALF07.
 55. The MBM of any one of claims 5 to 10, whereinthe CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences arethose of PALF08.
 56. The MBM of any one of claims 5 to 10, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofPALF09.
 57. The MBM of any one of claims 5 to 10, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF12.58. The MBM of any one of claims 5 to 10, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF13.
 59. TheMBM of any one of claims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences are those of PALF14.
 60. The MBM ofany one of claims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of PALF15.
 61. The MBM of any oneof claims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2and CDR-H3 sequences are those of PALF16.
 62. The MBM of any one ofclaims 5 to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of PALF17.
 63. The MBM of any one of claims 5to 10, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3sequences are those of PALF18.
 64. The MBM of any one of claims 5 to 10,wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequencesare those of PALF19.
 65. The MBM of any one of claims 5 to 10, whereinthe CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences arethose of PALF20.
 66. The MBM of any one of claims 11 to 18, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofAB3.
 67. The MBM of any one of claims 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of PI-61.68. The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-22. 69.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-88. 70.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-36. 71.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-34. 72.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-68. 73.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-18. 74.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-47. 75.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-20. 76.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-80. 77.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H₂/L2-83. 78.The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-1.
 79. TheMBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-2.
 80. The MBM ofany one of claims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of H3-3.
 81. The MBM of any one ofclaims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of H3-4.
 82. The MBM of any one of claims 11to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3sequences are those of H3-5.
 83. The MBM of any one of claims 11 to 18,wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequencesare those of H3-6.
 84. The MBM of any one of claims 11 to 18, whereinthe CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences arethose of H3-7.
 85. The MBM of any one of claims 11 to 18, wherein theCDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those ofH3-8.
 86. The MBM of any one of claims 11 to 18, wherein the CDR-L1,CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-9.87. The MBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2,CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-10.
 88. TheMBM of any one of claims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3,CDR-H1, CDR-H2 and CDR-H3 sequences are those of H3-11.
 89. The MBM ofany one of claims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2 and CDR-H3 sequences are those of H3-12.
 90. The MBM of any oneof claims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2and CDR-H3 sequences are those of H3-13.
 91. The MBM of any one ofclaims 11 to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 andCDR-H3 sequences are those of H3-14.
 92. The MBM of any one of claims 11to 18, wherein the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3sequences are those of H3-15.
 93. The MBM of claim 1 or claim 2, whereinABM1 comprises a light chain variable sequence set forth in Table 11O-1and the corresponding heavy chain variable sequence set forth in Table11O-2.
 94. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof AB1.
 95. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof AB2.
 96. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof AB3.
 97. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof R1F2.
 98. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF03.
 99. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF04.
 100. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF05.
 101. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF06.
 102. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF07.
 103. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF08.
 104. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF09.
 105. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF12.
 106. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF13.
 107. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF14.
 108. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF15.
 109. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF16.
 110. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF17.
 111. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF18.
 112. The MBM of claim 93, wherein the light chain variablesequence and the corresponding heavy chain variable sequence are thoseof PALF19. WO 2020/236795 PCT/US2020/033563
 113. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of PALF20.
 114. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of PI-61.
 115. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-88.
 116. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-36.
 117. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-34.
 118. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-68.
 119. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-18.
 120. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-47.
 121. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-20.
 122. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-80.
 123. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H₂/L2-83.
 124. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H3-1.
 125. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H3-2.
 126. The MBM of claim 93,wherein the light chain variable sequence and the corresponding heavychain variable sequence are those of H3-3. WO 2020/236795PCT/US2020/033563
 127. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-4.
 128. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-5.
 129. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-6.
 130. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-7.
 131. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-8.
 132. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-9.
 133. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-10.
 134. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-11.
 135. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-12.
 136. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-13.
 137. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-14.
 138. The MBM of claim 93, wherein the light chainvariable sequence and the corresponding heavy chain variable sequenceare those of H3-15.
 139. The MBM of any one of claims 1 to 138, whereinABM1 is an antibody, an antibody fragment, an scFv, a dsFv, a Fv, a Fab,an scFab, a (Fab′)2, or a single domain antibody (SDAB). WO 2020/236795PCT/US2020/033563
 140. The MBM of claim 139, wherein ABM1 comprises anantibody or an antigen- binding domain thereof.
 141. The MBM of claim139, wherein ABM1 comprises a scFv.
 142. The MBM of claim 141, whereinthe scFv of ABM1 comprises a sequence set forth in Table 11P.
 143. TheMBM of any one of claims 1 to 142, wherein ABM2 is a non-immunoglobulinscaffold based ABM.
 144. The MBM of any one of claims 1 to 142, whereinABM2 is an immunoglobulin scaffold based ABM.
 145. The MBM of any one ofclaims 1 to 144, wherein the component of the TCR complex is CD3. 146.The MBM of claim 145, wherein ABM2 comprises any of the bindingsequences set forth in any one of Tables 12A through 12D.
 147. The MBMof any one of claims 1 to 144, wherein the component of the TCR complexis TCR-α, TCR-β, a TCR-α/β dimer, TCR-γ, TCR-δ, or a TCR-γ/δ dimer. 148.The MBM of any one of claims 1 to 147, wherein ABM3 binds specificallyto human CD2.
 149. The MBM of claim 148, wherein ABM3 is anon-immunoglobulin scaffold based ABM.
 150. The MBM of claim 149,wherein ABM3 comprises a receptor binding domain of a CD2 ligand. 151.The MBM of claim 150, wherein ABM3 is a CD58 moiety.
 152. The MBM ofclaim 151, wherein the CD58 moiety comprises the amino acid sequence ofCD58-1 as set forth in Table
 15. 153. The MBM of claim 151, wherein theCD58 moiety comprises the amino acid sequence of CD58-2 as set forth inTable
 15. 154. The MBM of claim 151, wherein the CD58 moiety comprisesthe amino acid sequence of CD58-3 as set forth in Table
 15. WO2020/236795 PCT/US2020/033563
 155. The MBM of claim 151, wherein theCD58 moiety comprises the amino acid sequence of CD58-4 as set forth inTable
 15. 156. The MBM of claim 151, wherein the CD58 moiety comprisesthe amino acid sequence of CD58-5 as set forth in Table
 15. 157. The MBMof claim 151, wherein the CD58 moiety comprises the amino acid sequenceof CD58-6 as set forth in Table
 15. 158. The MBM of claim 151, whereinthe CD58 moiety comprises the amino acid sequence of CD58-7 as set forthin Table
 15. 159. The MBM of claim 151, wherein the CD58 moietycomprises the amino acid sequence of CD58-8 as set forth in Table 15.160. The MBM of claim 151, wherein the CD58 moiety comprises the aminoacid sequence of CD58-9 as set forth in Table
 15. 161. The MBM of claim151, wherein the CD58 moiety comprises the amino acid sequence ofCD58-10 as set forth in Table
 15. 162. The MBM of claim 151, wherein theCD58 moiety comprises the amino acid sequence of CD58-11 as set forth inTable
 15. 163. The MBM of claim 150, wherein ABM3 is a CD48 moiety. 164.The MBM claim 148, wherein ABM3 is an immunoglobulin scaffold based ABM.165. The MBM of any one of claims 1 to 147, wherein ABM3 bindsspecifically to a human TAA.
 166. The MBM of claim 165, wherein ABM3 isa non-immunoglobulin scaffold based ABM.
 167. The MBM of claim 165,wherein ABM3 is an immunoglobulin scaffold based ABM.
 168. The MBM ofclaims 165 to 167, wherein the TAA is a TAA expressed on cancerous Bcells that are B cell-derived plasma cells.
 169. The MBM of claims 165to 167, wherein the TAA is a TAA expressed on cancerous B cells that arenot plasma cells. WO 2020/236795 PCT/US2020/033563
 170. The MBM ofclaims 165 to 169, wherein the TAA is selected from CD19, CD20, CD22,CD123, CD33, CLL1, CD138, CS1, CD38, CD133, FLT3, CD52, TNFRSF13C,TNFRSF13B, CXCR4, PD-L1, LY9, CD200, FCGR2B, CD21, CD23, CD24, CD4OL,CD72, CD79a, and CD79b.
 171. The MBM of claim 167, wherein ABM3comprises a binding sequence set forth in Table 16 or Table
 17. 172. TheMBM of any one of claims 1 to 171 which comprises an Fc domain.
 173. TheMBM of claim 172, wherein the Fc domain is an Fc heterodimer.
 174. TheMBM of claim 173, wherein the Fc heterodimer comprises any of the Fcmodifications set forth in Table
 3. 175. The MBM of any one of claims172 to 174, wherein the Fc domain has altered effector function. 176.The MBM of any one of claims 1 to 175, which is a trivalent MBM. 177.The MBM of claim 176, wherein the trivalent MBM has any one of theconfigurations depicted in FIGS. 1B-1P.
 178. The MBM of any one ofclaims 1 to 175, which is a tetravalent MBM.
 179. The MBM of claim 178,wherein the tetravalent MBM has any one of the configurations depictedin FIGS. 1Q-1S.
 180. The MBM of any one of claims 1 to 175, which is apentavalent MBM.
 181. The MBM of claim 180, wherein the pentavalent MBMhas the configuration depicted in FIG. 1T.
 182. The MBM of any one ofclaims 1 to 175, which is a hexavalent MBM.
 183. The MBM of claim 182,wherein the hexavalent MBM has the configuration depicted in FIG. 1U orFIG. 1V.
 184. The MBM of any one of claims 1 to 183, wherein eachantigen-binding module is capable of binding its respective target atthe same time as each of the other antigen-binding modules is bound toits respective target. WO 2020/236795 PCT/US2020/033563
 185. The MBM ofany one of claims 1 to 184, wherein the MBM is a trispecific bindingmolecule (TBM).
 186. A conjugate comprising the MBM of any one of claims1 to 185, and an agent, optionally a therapeutic agent, a diagnosticagent, a masking moiety, a cleavable moiety, or any combination thereof.187. A preparation of MBMs comprising a plurality of MBMs moleculesaccording to any one of claims 1 to 185 or a plurality of conjugatemolecules according claim 186, optionally wherein the pluralitycomprises at least 100, at least 1,000, at least 10,000, or at least100,000 MBM molecules or conjugate molecules.
 188. A pharmaceuticalcomposition comprising the MBM of any one of claims 1 to 185, theconjugate of claim 186, or the preparation of any one claim 187, and anexcipient.
 189. A method of treating a subject having a disease ordisorder associated with expression of BCMA, comprising administering toa subject an effective amount of the MBM of any one of claims 1 to 185,the conjugate of claim 186, the preparation of claim 187, or thepharmaceutical composition of claim
 188. 190. The method of claim 189,wherein the disease or disorder comprises a cancer.
 191. The method ofclaim 190, wherein the cancer comprises a B cell malignancy.
 192. Themethod of claim 191, wherein when the MBM is a MBM that bindsspecifically to a TAA, the B cell malignancy comprises cancerous B cellsexpressing both BCMA and the TAA.
 193. The method of claim 191, whereinwhen the MBM is a MBM that binds specifically to a TAA, the B cellmalignancy comprises cancerous B cells expressing BCMA, but not the TAA,and cancerous B cells expressing the TAA, but not BCMA.
 194. The methodof any one of claims 191 to 193, wherein the B cell malignancy isselected from selected from Hodgkin's lymphoma, non-Hodgkin's lymphomaand multiple myeloma.
 195. The method of any one of claims 190 to 194,further comprising administering at least one additional agent to thesubject. WO 2020/236795 PCT/US2020/033563
 196. The method of claim 189,wherein the disease or disorder is an autoimmune disorder.
 197. Themethod of claim 196, wherein the autoimmune disorder is selected fromsystemic lupus erythematosus (SLE), Sjogren's syndrome, scleroderma,rheumatoid arthritis (RA), juvenile idiopathic arthritis, graft versushost disease, dermatomyositis, type I diabetes mellitus, Hashimoto'sthyroiditis, Graves's disease, Addison's disease, celiac disease,Crohn's Disease, pernicious anaemia, pemphigus vulgaris, vitiligo,autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura,giant cell arteritis, myasthenia gravis, multiple sclerosis (MS) (e.g.,relapsing-remitting MS (RRMS)), glomerulonephritis, Goodpasture'ssyndrome, bullous pemphigoid, colitis ulcerosa, Guillain-Barré syndrome,chronic inflammatory demyelinating polyneuropathy, anti-phospholipidsyndrome, narcolepsy, sarcoidosis, and Wegener's granulomatosis.
 198. Anucleic acid or plurality of nucleic acids encoding the MBM of any oneof claims 1 to
 185. 199. A cell engineered to express the MBM of any oneof claims 1 to
 185. 200. A cell transfected with one or more expressionvectors comprising one or more nucleic acid sequences encoding the MBMof any one of claims 1 to 185 under the control of one or morepromoters.
 201. A method of producing a MBM, comprising: (a) culturingthe cell of claim 199 or claim 200 in conditions under which the MBM isexpressed; and (b) recovering the MBM from the cell culture.